Heterocyclic compounds as immunomodulators

ABSTRACT

Disclosed are compounds of Formula (I), methods of using the compounds as immunomodulators, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders such as cancer or infections.

FIELD OF THE INVENTION

The present application is concerned with pharmaceutically activecompounds. The disclosure provides compounds as well as theircompositions and methods of use. The compounds modulate PD-1/PD-L1protein/protein interaction and are useful in the treatment of variousdiseases including infectious diseases and cancer.

BACKGROUND OF THE INVENTION

The immune system plays an important role in controlling and eradicatingdiseases such as cancer. However, cancer cells often develop strategiesto evade or to suppress the immune system in order to favor theirgrowth. One such mechanism is altering the expression of costimulatoryand co-inhibitory molecules expressed on immune cells (Postow et al, J.Clinical Oncology 2015, 1-9). Blocking the signaling of an inhibitoryimmune checkpoint, such as PD-1, has proven to be a promising andeffective treatment modality.

Programmed cell death-1 (PD-1), also known as CD279, is a cell surfacereceptor expressed on activated T cells, natural killer T cells, Bcells, and macrophages (Greenwald et al, Annu. Rev. Immunol 2005,23:515-548; Okazaki and Honjo, Trends Immunol 2006, (4):195-201). Itfunctions as an intrinsic negative feedback system to prevent theactivation of T-cells, which in turn reduces autoimmunity and promotesself-tolerance. In addition, PD-1 is also known to play a critical rolein the suppression of antigen-specific T cell response in diseases likecancer and viral infection (Sharpe et al, Nat Immunol 2007 8, 239-245;Postow et al, J. Clinical Oncol 2015, 1-9).

The structure of PD-1 consists of an extracellular immunoglobulinvariable-like domain followed by a transmembrane region and anintracellular domain (Parry et al, Mol Cell Biol 2005, 9543-9553). Theintracellular domain contains two phosphorylation sites located in animmunoreceptor tyrosine-based inhibitory motif and an immunoreceptortyrosine-based switch motif, which suggests that PD-1 negativelyregulates T cell receptor-mediated signals. PD-1 has two ligands, PD-L1and PD-L2 (Parry et al, Mol Cell Biol 2005, 9543-9553; Latchman et al,Nat Immunol 2001, 2, 261-268), and they differ in their expressionpatterns. PD-L1 protein is upregulated on macrophages and dendriticcells in response to lipopolysaccharide and GM-CSF treatment, and on Tcells and B cells upon T cell receptor and B cell receptor signaling.PD-L1 is also highly expressed on almost all tumor cells, and theexpression is further increased after IFN-γtreatment (Iwai et al, PNAS2002, 99(19):12293-7; Blank et al, Cancer Res 2004, 64(3):1140-5). Infact, tumor PD-L1 expression status has been shown to be prognostic inmultiple tumor types (Wang et al, Eur J Surg Oncol 2015; Huang et al,Oncol Rep 2015; Sabatier et al, Oncotarget 2015, 6(7): 5449-5464). PD-L2expression, in contrast, is more restricted and is expressed mainly bydendritic cells (Nakae et al, J Immunol 2006, 177:566-73). Ligation ofPD-1 with its ligands PD-L1 and PD-L2 on T cells delivers a signal thatinhibits IL-2 and IFN-γ production, as well as cell proliferationinduced upon T cell receptor activation (Carter et al, Eur J Immunol2002, 32(3):634-43; Freeman et al, J Exp Med 2000, 192(7):1027-34). Themechanism involves recruitment of SHP-2 or SHP-1 phosphatases to inhibitT cell receptor signaling such as Syk and Lck phosphorylation (Sharpe etal, Nat Immunol 2007, 8, 239-245). Activation of the PD-1 signaling axisalso attenuates PKC-θ activation loop phosphorylation, which isnecessary for the activation of NF-κB and AP1 pathways, and for cytokineproduction such as IL-2, IFN-γ and TNF (Sharpe et al, Nat Immunol 2007,8, 239-245; Carter et al, Eur J Immunol 2002, 32(3):634-43; Freeman etal, J Exp Med 2000, 192(7):1027-34).

Several lines of evidence from preclinical animal studies indicate thatPD-1 and its ligands negatively regulate immune responses.PD-1-deficient mice have been shown to develop lupus-likeglomerulonephritis and dilated cardiomyopathy (Nishimura et al, Immunity1999, 11:141-151; Nishimura et al, Science 2001, 291:319-322). Using anLCMV model of chronic infection, it has been shown that PD-1/PD-L1interaction inhibits activation, expansion and acquisition of effectorfunctions of virus-specific CD8 T cells (Barber et al, Nature 2006, 439,682-7). Together, these data support the development of a therapeuticapproach to block the PD-1-mediated inhibitory signaling cascade inorder to augment or “rescue” T cell response. Accordingly, there is aneed for new compounds that block PD-1/PD-L1 protein/proteininteraction.

SUMMARY

The present disclosure provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinconstituent variables are defined herein. The present disclosure furtherprovides a pharmaceutical composition comprising a compound disclosedherein, or a pharmaceutically acceptable salt or a stereoisomer thereof,and one or more pharmaceutically acceptable excipient or carrier.

The present disclosure further provides methods of inhibiting PD-1/PD-L1interaction, said method comprising administering to a patient acompound disclosed herein, or a pharmaceutically acceptable salt or astereoisomer thereof.

The present disclosure further provides methods of treating a disease ordisorder associated with inhibition of PD-1/PD-L1 interaction, saidmethod comprising administering to a patient in need thereof atherapeutically effective amount of a compound of disclosed herein, or apharmaceutically acceptable salt or a stereoisomer thereof.

The present disclosure further provides methods of enhancing,stimulating and/or increasing the immune response in a patient, saidmethod comprising administering to the patient in need thereof atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt or a stereoisomer thereof.

DETAILED DESCRIPTION I. Compounds

The present disclosure provides, inter alia, compounds of Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein:

ring A is 5- to 14-membered heteroaryl, 4- to 14-memberedheterocycloalkyl, C₆₋₁₀ aryl or C₃₋₁₄ cycloalkyl, wherein the 5- to14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each has1-4 heteroatoms as ring members selected from B, P, N, O and S, whereinthe P, N or S atom as ring members is optionally oxidized and one ormore carbon atoms as ring members are each optionally replaced by acarbonyl group; and wherein ring A is optionally substituted with 1, 2,3, 4 or 5 R⁶ substituents;

L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, —C(═S)NR¹³—, —NR¹³C(═S)—,—C(═NR¹³)NR¹³—, —NR¹³C(═NR¹³)—, —C(═NOR¹³)NR¹³—, —NR¹³C(═NOR¹³)—,—C(═NCN)NR¹³—, —NR¹³C(═NCN)—, O, —(CR¹⁴R¹⁵)_(q)—, —(CR¹⁴R¹⁵)_(q)—O—,—O(CR¹⁴R¹⁵)_(q)—, —NR¹³—, —(CR¹⁴R¹⁵)_(q)—NR¹³—, —NR¹³—(CR¹⁴R¹⁵)_(q)—,—CH═CH—, —C≡C—, —SO₂NR¹³—, —NR¹³SO₂—, —NR¹³SO₂NR¹³—, —NR¹³C(O)O—,—OC(O)NR¹³— or —NR¹³C(O)NR¹³—;

R³ is methyl, halo, CN or C₁₋₄ haloalkyl;

R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁶ and R¹⁷ are each independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), C(O)NR^(a)S(O)₂R^(a),OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a),NR^(a)C(═NR^(a))R^(a), NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a),C(═NR^(a))R^(a), C(═NOH)R^(a), C(═NOH)NR^(a), C(═NCN)NR^(a)R^(a),NR^(a)C(═NCN)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a),S(O)₂NR^(a)C(O)R^(a), —P(O)R^(a)R^(a), —P(O)(OR^(a))(OR^(a)), —B(OH)₂,—B(OR^(a))₂ and S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl,4-14 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14membered heterocycloalkyl)-C₁₋₄ alkyl- of R⁶ and R¹⁷ are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents;

or two R⁶ substituents attached to the same ring carbon atom takentogether with the ring carbon atom to which they are attached form spiroC₃₋₆ cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each ofwhich is optionally substituted with 1, 2, or 3 independently selectedR^(f) substituents;

each R¹³ is independently H, C₁₋₆ haloalkyl or C₁₋₆ alkyl optionallysubstituted with a substituent selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyland —N(C₁₋₄ alkyl)₂;

R¹⁴ and R¹⁵ are each independently selected from H, halo, CN, OH, —COOH,C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and4-6 membered heterocycloalkyl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl of R¹⁴ or R¹⁵ are eachoptionally substituted with 1, 2, or 3 independently selected R^(q)substituents;

or R¹⁴ and R¹⁵ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5-, 6- or7-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 independently selected R^(q) substituents;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl,5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-14 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 independently selected R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₄ cycloalkyl, 4-14membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), C(O)NR^(e)S(O)₂R^(e),OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(═NR^(e))R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), S(O)₂NR^(e)C(O)R^(e), NR^(e)S(O)₂R^(e),NR^(e)S(O)₂NR^(e)R^(e), —P(O)R^(e)R^(e), —P(O)(OR^(e))(OR^(e)), —B(OH)₂,—B(OR^(e))₂ and S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, 5-14 membered heteroaryl, C₃₋₁₄ cycloalkyl, 4-14membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are each optionally substitutedwith 1, 2, or 3 independently selected R^(f) substituents;

each R^(e) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(e) are each optionally substituted with 1, 2 or 3 independentlyselected R^(f) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), C(O)NR^(c)S(O)₂R^(c),OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NOH)R^(c), C(═NOH)NR^(c),C(═NCN)NR^(c)R^(c), NR^(c)C(═NCN)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(═NR^(c))R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c),NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c),S(O)NR^(c)R^(c), S(O)₂R^(c), S(O)₂NR^(c)C(O)R^(c), —P(O)R^(c)R^(c),—P(O)(OR^(c))(OR^(c)), —B(OH)₂, —B(OR^(c))₂ and S(O)₂NR^(c)R^(c);wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each furtheroptionally substituted with 1, 2 or 3 independently selected R^(d)substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(f) substituents;

each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g),C(O)NR^(g)S(O)₂R^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g),NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(═NR^(g))R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),S(O)₂NR^(g)C(O)R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g),—P(O)R^(g)R^(g), —P(O)(OR^(g))(OR^(g)), —B(OH)₂, —B(OR^(g))₂ andS(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are eachoptionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(n) substituents;

each R^(n) is substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,halo, CN, NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o),C(O)OR^(o), C(O)NR^(o)S(O)₂R^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o),NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(═NR^(o))R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR^(o))NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),S(O)₂NR^(o)C(O)R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o),—P(O)R^(o)R^(o), —P(O)(OR^(o))(OR^(o)), —B(OH)₂, —B(OR^(o))₂ andS(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(n) are eachoptionally substituted with 1, 2 or 3 independently selected R^(q)substituents;

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1, 2, or 3 independently selected R^(p)substituents;

each R^(p) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(r),OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r),C(O)NR^(r)S(O)₂R^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r),NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(═NR^(r))R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),S(O)₂NR^(r)C(O)R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r),—P(O)R^(r)R^(r), —P(O)(OR^(r))(OR^(r)), —B(OH)₂, —B(OR^(r))₂ andS(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(p) is optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents;

or any two R^(a) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2or 3 independently selected R^(h) substituents;

each R^(h) is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN,OR^(i), SR^(i), NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i),C(O)NR^(i)S(O)₂R^(i), OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i),NR^(i)R^(i), NR^(i)C(O)R^(i), NR^(i)C(═NR^(i))R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),S(O)₂NR^(i)C(O)R^(i), NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i),—P(O)R^(i)R^(i), —P(O)(OR^(i))(OR^(i)), —B(OH)₂, —B(OR^(i))₂ andS(O)₂NR^(i)R^(i), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(h) are each further optionallysubstituted by 1, 2, or 3 independently selected R^(j) substituents;

each R^(j) is independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,NHOR^(k), OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k),C(O)NR^(k)S(O)₂R^(k), OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k),NR^(k)R^(k), NR^(k)C(O)R^(k), NR^(k)C(═NR^(k)k)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),S(O)₂NR^(k)C(O)R^(k), NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k),—P(O)R^(k)R^(k), —P(O)(OR^(k))(OR^(k)), —B(OH)₂, —B(OR^(k))₂ andS(O)₂NR^(k)R^(k), wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl,5- or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, and C₁₋₄ haloalkoxy of R^(j) areeach optionally substituted with 1, 2 or 3 independently selected R^(q)substituents;

or two R^(h) groups attached to the same carbon atom of the 4- to10-membered heterocycloalkyl taken together with the carbon atom towhich they are attached form a C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S;

-   -   or any two R^(c) substituents together with the boron,        phosphorus or nitrogen atom to which they are attached form a        4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group        optionally substituted with 1, 2, or 3 independently selected        R^(h) substituents;

or any two R^(e) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(h) substituents;

or any two R^(g) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(h) substituents;

or any two R^(i) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(h) substituents, or 1, 2, or 3independently selected R^(q) substituents;

or any two R^(k) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(h) substituents, or 1, 2, or 3independently selected R^(q) substituents;

or any two R^(o) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(h) substituents;

or any two R^(r) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(h) substituents;

each R^(i), R^(k), R^(o) or R^(r) is independently selected from H, C₁₋₄alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7membered heterocycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₄alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl,C₂₋₄ alkenyl, and C₂₋₄ alkynyl of R^(i), R^(k), R^(o) or R^(r) are eachoptionally substituted with 1, 2 or 3 independently selected R^(q)substituents;

each R^(q) is independently selected from halo, OH, CN, —COOH, NH₂,—NH—C₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, phenyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl and C₃₋₆ cycloalkyl, whereinthe C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl,and 5-6 membered heteroaryl of R^(q) are each optionally substitutedwith 1, 2 or 3 substituents independently selected from halo, OH, CN,—COOH, NH₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,phenyl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl;

the subscript m is an integer of 0, 1, 2 or 3;

the subscript n is an integer of 0, 1, 2 or 3;

each subscript q is independently an integer of 1, 2, 3 or 4; and

the subscript s is an integer of 1, 2, 3 or 4.

In some embodiments, the present disclosure provides compounds ofFormula (I), or a pharmaceutically acceptable salt or a stereoisomerthereof, wherein:

ring A is 5- to 14-membered heteroaryl, 4- to 14-memberedheterocycloalkyl, C₆₋₁₀ aryl or C₃₋₁₄ cycloalkyl, wherein the 5- to14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each has1-4 heteroatoms as ring members selected from B, P, N, O and S, whereinthe P, N or S atom as ring members is optionally oxidized and one ormore carbon atoms as ring members are each optionally replaced by acarbonyl group; and wherein ring A is optionally substituted with 1, 2,3, 4 or 5 R⁶ substituents;

L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, O, —(CR¹⁴R¹⁵)_(q)—,—(CR¹⁴R¹⁵)_(q)—O—, —O(CR¹⁴R¹⁵)_(q)—, —NR¹³—, —(CR¹⁴R¹⁵)_(q)—NR¹³—,—NR¹³—(CR¹⁴R¹⁵)_(q)—, —CH═CH—, —C≡C—, —SO₂NR¹³—, —NR¹³SO₂—,—NR¹³SO₂NR¹³—, —NR¹³C(O)O—, —OC(O)NR¹³— or —NR¹³C(O)NR¹³—;

R³ is methyl, halo, CN or C₁₋₄ haloalkyl;

R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁶ and R¹⁷ are each independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NOH)R^(a), C(═NOH)NR^(a),C(═NCN)NR^(a)R^(a), NR^(a)C(═NCN)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a),—P(O)R^(a)R^(a), —P(O)(OR^(a))(OR^(a)), —B(OH)₂, —B(OR^(a))₂ andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁶ and R¹⁷ are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents;

or two R⁶ substituents attached to the same ring carbon atom takentogether with the ring carbon atom to which they are attached form spiroC₃₋₆ cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each ofwhich is optionally substituted with 1, 2, or 3 independently selectedR^(f) substituents;

each R¹³ is independently H, C₁₋₆ haloalkyl or C₁₋₆ alkyl optionallysubstituted with a substituent selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyland —N(C₁₋₄ alkyl)₂;

R¹⁴ and R¹⁵ are each independently selected from H, halo, CN, OH, —COOH,C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and4-6 membered heterocycloalkyl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl of R¹⁴ or R¹⁵ are eachoptionally substituted with 1, 2, or 3 independently selected R^(q)substituents;

or R¹⁴ and R¹⁵ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5-, 6- or7-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 independently selected R^(q) substituents;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl,5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-14 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 independently selected R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₄ cycloalkyl, 4-14membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),—P(O)R^(e)R^(e), —P(O)(OR^(e))(OR^(e)), —B(OH)₂, —B(OR^(e))₂ andS(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,5-14 membered heteroaryl, C₃₋₁₄ cycloalkyl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are each optionally substitutedwith 1, 2, or 3 independently selected R^(f) substituents;

each R^(e) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(e) are each optionally substituted with 1, 2 or 3 independentlyselected R^(f) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NOH)R^(c), C(═NOH)NR^(c), C(═NCN)NR^(c)R^(c),NR^(c)C(═NCN)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c), —P(O)R^(c)R^(c), —P(O)(OR^(c))(OR^(c)), —B(OH)₂, —B(OR^(c))₂and S(O)₂NR^(c)R^(c); wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(b) are each further optionally substituted with 1, 2 or 3independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(f) substituents;

each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), —P(O)R^(g)R^(g),—P(O)(OR^(g)g)(OR^(g)g), —B(OH)₂, —B(OR^(g))₂ and S(O)₂NR^(g)R^(g);wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 independently selected R^(n) substituents;

-   -   each R^(n) is substituents independently selected from C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,        C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(o), OR^(o),        SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o),        OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),        NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR^(o))NR^(o)R^(o),        NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o),        S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o),        —P(O)R^(o)R^(o), —P(O)(OR^(o))(OR^(o)), —B(OH)₂, —B(OR^(o))₂ and        S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R^(n) are each optionally        substituted with 1, 2 or 3 independently selected R^(q)        substituents;

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1, 2, or 3 independently selected R^(p)substituents;

each R^(p) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(r),OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r),OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r), —P(O)R^(r)R^(r),—P(O)(OR^(r))(OR^(r)), —B(OH)₂, —B(OR^(r))₂ and S(O)₂NR^(r)R^(r),wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(p) is optionally substituted with 1,2 or 3 independently selected R^(q) substituents;

or any two R^(a) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2or 3 independently selected R^(h) substituents;

each R^(h) is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN,OR^(i), SR^(i), NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i),OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), —P(O)R^(i)R^(i),—P(O)(OR^(i))(OR^(i)), —B(OH)₂, —B(OR^(i))₂ and S(O)₂NR^(i)R^(i),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- ofR^(h) are each further optionally substituted by 1, 2, or 3independently selected R^(j) substituents;

each R^(j) is independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,NHOR^(k), OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k),OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR)NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), —P(O)R^(k)R^(k),—P(O)(OR^(k))(OR^(k)), —B(OH)₂, —B(OR^(k))₂ and S(O)₂NR^(k)R^(k),wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-memberedheteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy of R^(j) are each optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents;

or two R^(h) groups attached to the same carbon atom of the 4- to10-membered heterocycloalkyl taken together with the carbon atom towhich they are attached form a C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S;

or any two R^(c) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(h) substituents;

or any two R^(e) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(h) substituents;

or any two R^(g) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(h) substituents;

or any two R^(i) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(h) substituents, or 1, 2, or 3independently selected R^(q) substituents;

or any two R^(k) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(h) substituents, or 1, 2, or 3independently selected R^(q) substituents;

or any two R^(o) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(h) substituents;

or any two R^(r) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(h) substituents;

each R^(i), R^(k), R^(o) or R^(r) is independently selected from H, C₁₋₄alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7membered heterocycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₄alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl,C₂₋₄ alkenyl, and C₂₋₄ alkynyl of R^(i), R^(k), R^(o) or R^(r) are eachoptionally substituted with 1, 2 or 3 independently selected R^(q)substituents;

each R^(q) is independently selected from halo, OH, CN, —COOH, NH₂,—NH—C₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, phenyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl and C₃₋₆ cycloalkyl, whereinthe C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl,and 5-6 membered heteroaryl of R^(q) are each optionally substitutedwith 1, 2 or 3 substituents independently selected from halo, OH, CN,—COOH, NH₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,phenyl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl;

the subscript m is an integer of 0, 1, 2 or 3;

the subscript n is an integer of 0, 1, 2 or 3;

each subscript q is independently an integer of 1, 2, 3 or 4; and

the subscript s is an integer of 1, 2, 3 or 4.

In some embodiments, the present disclosure provides compounds ofFormula (I), or a pharmaceutically acceptable salt or a stereoisomerthereof, wherein:

ring A is 5- to 14-membered heteroaryl, 4- to 14-memberedheterocycloalkyl, C₆₋₁₀ aryl or C₃₋₁₄ cycloalkyl, wherein the 5- to14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each has1-4 heteroatoms as ring members selected from B, P, N, O and S, whereinthe P, N or S atom as ring members is optionally oxidized and one ormore carbon atoms as ring members are each optionally replaced by acarbonyl group; and wherein ring A is optionally substituted with 1, 2,3, 4 or 5 R⁶ substituents;

L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, O, —(CR¹⁴R¹⁵)_(q)—,—(CR¹⁴R¹⁵)_(q)—O—, —O(CR¹⁴R¹⁵)_(q)—, —NR¹³—, —(CR¹⁴R¹⁵)_(q)—NR¹³—,—NR¹³—(CR¹⁴R¹⁵)_(q), —CH═CH—, —C≡C—, —SO₂NR¹³—, —NR¹³SO₂—,—NR¹³SO₂NR¹³—, —NR¹³C(O)O—, —OC(O)NR¹³— or —NR¹³C(O)NR¹³—;

R³ is methyl, halo, CN or C₁₋₄ haloalkyl;

R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁶ and R¹⁷ are each independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NOH)R^(a), C(═NOH)NR^(a),C(═NCN)NR^(a)R^(a), NR^(a)C(═NCN)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a),—P(O)R^(a)R^(a), —P(O)(OR^(a))(OR^(a)), —B(OH)₂, —B(OR^(a))₂ andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁶ and R¹⁷ are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents;

or two R⁶ substituents attached to the same ring carbon atom takentogether with the ring carbon atom to which they are attached form spiroC₃₋₆ cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each ofwhich is optionally substituted with 1, 2, or 3 independently selectedR^(f) substituents;

each R¹³ is independently H, C₁₋₆ haloalkyl or C₁₋₆ alkyl optionallysubstituted with a substituent selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyland —N(C₁₋₄ alkyl)₂;

R¹⁴ and R¹⁵ are each independently selected from H, halo, CN, OH, —COOH,C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and4-6 membered heterocycloalkyl, wherein the C₁₋₄ alkyl, C₁. 4 alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl of R¹⁴ or R¹⁵ are eachoptionally substituted with 1, 2, or 3 independently selected R^(q)substituents;

or R¹⁴ and R¹⁵ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5-, 6- or7-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 independently selected R^(q) substituents;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl,5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-14 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 independently selected R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₄ cycloalkyl, 4-14membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),—P(O)R^(e)R^(e), —P(O)(OR^(e))(OR^(e)), —B(OH)₂, —B(OR^(e))₂ andS(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,5-14 membered heteroaryl, C₃₋₁₄ cycloalkyl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are each optionally substitutedwith 1, 2, or 3 independently selected R^(f) substituents;

each R^(e) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(e) are each optionally substituted with 1, 2 or 3 independentlyselected R^(f) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NOH)R^(c), C(═NOH)NR^(c), C(═NCN)NR^(c)R^(c),NR^(c)C(═NCN)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c), —P(O)R^(c)R^(c), —P(O)(OR^(c))(OR^(c)), —B(OH)₂, —B(OR^(c))₂and S(O)₂NR^(c)R^(c); wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(b) are each further optionally substituted with 1, 2 or 3independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(f) substituents;

each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), —P(O)R^(g)R^(g),—P(O)(OR^(g))(OR^(g)), —B(OH)₂, —B(OR^(g))₂ and S(O)₂NR^(g)R^(g);wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 independently selected R^(n) substituents;

each R^(n) is substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,halo, CN, NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o),C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o),NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o),S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o),—P(O)R^(o)R^(o), —P(O)(OR^(o))(OR^(o)), —B(OH)₂, —B(OR^(o))₂ andS(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(n) are eachoptionally substituted with 1, 2 or 3 independently selected R^(q)substituents;

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1, 2, or 3 independently selected R^(p)substituents;

each R^(p) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(r),OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r),OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR)NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r), —P(O)R^(r)R^(r),—P(O)(OR^(r))(OR^(r)), —B(OH)₂, —B(OR^(r))₂ and S(O)₂NR^(r)R^(r),wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(p) is optionally substituted with 1,2 or 3 independently selected R^(q) substituents;

or any two R^(a) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2or 3 independently selected R^(h) substituents;

each R^(h) is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN,OR^(i), SR^(i), NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i),OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i) S(O)₂NR^(i)R^(i), —P(O)R^(i)R^(i),—P(O)(OR^(i))(OR^(i)), —B(OH)₂, —B(OR^(i))₂ and S(O)₂NR^(i)R^(i),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- ofR^(h) are each further optionally substituted by 1, 2, or 3independently selected R^(j) substituents;

each R^(j) is independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,NHOR^(k), OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k),OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR)NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), —P(O)R^(k)R^(k),—P(O)(OR^(k))(OR^(k)), —B(OH)₂, —B(OR^(k))₂ and S(O)₂NR^(k)R^(k),wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-memberedheteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy of R^(j) are each optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents;

or two R^(h) groups attached to the same carbon atom of the 4- to10-membered heterocycloalkyl taken together with the carbon atom towhich they are attached form a C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S;

or any two R^(c) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(h) substituents;

or any two R^(e) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(h) substituents;

or any two R^(g) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(h) substituents;

or any two R^(i) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(q) substituents;

or any two R^(k) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(q) substituents;

or any two R^(o) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(h) substituents;

or any two R^(r) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(h) substituents;

each R^(i), R^(k), R^(o) or R^(r) is independently selected from H, C₁₋₄alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7membered heterocycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₄alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl,C₂₋₄ alkenyl, and C₂₋₄ alkynyl of R^(i), R^(k), R^(o) or R^(r) are eachoptionally substituted with 1, 2 or 3 independently selected R^(q)substituents;

each R^(q) is independently selected from halo, OH, CN, —COOH, NH₂,—NH—C₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, phenyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl and C₃₋₆ cycloalkyl, whereinthe C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl,and 5-6 membered heteroaryl of R^(q) are each optionally substitutedwith 1, 2 or 3 substituents independently selected from halo, OH, CN,—COOH, NH₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,phenyl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl;

the subscript m is an integer of 0, 1, 2 or 3;

the subscript n is an integer of 0, 1, 2 or 3;

each subscript q is independently an integer of 1, 2, 3 or 4; and

the subscript s is an integer of 1, 2, 3 or 4.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or a stereoisomer thereof, wherein:

ring A is 5- to 14-membered heteroaryl, 4- to 14-memberedheterocycloalkyl, C₆₋₁₀ aryl or C₃₋₁₄ cycloalkyl, wherein the 5- to14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each has1-4 heteroatoms as ring members selected from N, O and S, wherein the Nor S atom as ring members is optionally oxidized and one or more carbonatoms as ring members are each optionally replaced by a carbonyl group;and wherein ring A is optionally substituted with 1, 2, 3, 4 or 5 R⁶substituents;

L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, O, —(CR¹⁴R¹⁵)_(q)—,—(CR¹⁴R¹⁵)_(q)—O—, —O(CR¹⁴R¹⁵)_(q)—, —NR¹³—, —(CR¹⁴R¹⁵)_(q)—NR¹³—,—NR¹³—(CR¹⁴R¹⁵)_(q)—, —CH═CH—, —C≡C—, —SO₂NR¹³—, —NR¹³SO₂,—NR¹³SO₂NR¹³—, —NR¹³C(O)O—, —OC(O)NR¹³— or —NR¹³C(O)NR¹³—;

R³ is methyl, halo, CN or C₁₋₄ haloalkyl;

R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁶ and R¹⁷ are each independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NOH)R^(a), C(═NOH)NR^(a),C(═NCN)NR^(a)R^(a), NR^(a)C(═NCN)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁶ and R¹⁷ are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents;

or two R⁶ substituents attached to the same ring carbon atom takentogether with the ring carbon atom to which they are attached form spiroC₃₋₆ cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each ofwhich is optionally substituted with 1, 2, or 3 independently selectedR^(f) substituents;

each R¹³ is independently H, C₁₋₆ haloalkyl or C₁₋₆ alkyl optionallysubstituted with a substituent selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyland —N(C₁₋₄ alkyl)₂;

R¹⁴ and R¹⁵ are each independently selected from H, halo, CN, OH, —COOH,C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and4-6 membered heterocycloalkyl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl of R¹⁴ or R¹⁵ are eachoptionally substituted with 1, 2, or 3 independently selected R^(q)substituents;

or R¹⁴ and R¹⁵ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5-, 6- or7-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 independently selected R^(q) substituents;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl,5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-14 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 independently selected R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₄ cycloalkyl, 4-14membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),and S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, 5-14 membered heteroaryl, C₃₋₁₄ cycloalkyl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are each optionally substitutedwith 1, 2, or 3 independently selected R^(f) substituents;

each R^(e) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(e) are each optionally substituted with 1, 2 or 3 independentlyselected R^(f) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NOH)R^(c), C(═NOH)NR^(c), C(═NCN)NR^(c)R^(c),NR^(c)C(═NCN)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c); wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(b) are each further optionally substituted with 1, 2 or 3independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(f) substituents;

each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 independently selected R^(n) substituents;

each R^(n) is substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,halo, CN, NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o),C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o),NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o),S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o),and S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(n) are eachoptionally substituted with 1, 2 or 3 independently selected R^(q)substituents;

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1, 2, or 3 independently selected R^(p)substituents;

each R^(p) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(r),OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r),OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR)NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) and S(O)₂NR^(r)R^(r), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(p) is optionally substituted with 1,2 or 3 independently selected R^(q) substituents;

or any two R^(a) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3independently selected R^(h) substituents;

each R^(h) is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN,OR^(i), SR^(i), NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i),OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- ofR^(h) are each further optionally substituted by 1, 2, or 3independently selected R^(j) substituents;

each R^(j) is independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,NHOR^(k), OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k),OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR)NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k), whereinthe C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-memberedheteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy of R^(j) are each optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents;

or two R^(h) groups attached to the same carbon atom of the 4- to10-membered heterocycloalkyl taken together with the carbon atom towhich they are attached form a C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents, or 1, 2 or 3 independentlyselected R^(q) substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents, or 1, 2 or 3 independentlyselected R^(q) substituents;

or any two R^(o) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(r) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

each R^(i), R^(k), R^(o) or R^(r) is independently selected from H, C₁₋₄alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7membered heterocycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₄alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl,C₂₋₄ alkenyl, and C₂₋₄ alkynyl of R^(i), R^(k), R^(o) or R^(r) are eachoptionally substituted with 1, 2 or 3 independently selected R^(q)substituents;

each R^(q) is independently selected from halo, OH, CN, —COOH, NH₂,—NH—C₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, phenyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl and C₃₋₆ cycloalkyl, whereinthe C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl,and 5-6 membered heteroaryl of R^(q) are each optionally substitutedwith 1, 2 or 3 substituents independently selected from halo, OH, CN,—COOH, NH₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,phenyl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl;

the subscript m is an integer of 0, 1, 2 or 3;

the subscript n is an integer of 0, 1, 2 or 3;

each subscript q is independently an integer of 1, 2, 3 or 4; and

the subscript s is an integer of 1, 2, 3 or 4.

In some embodiments, the present disclosure provides compounds ofFormula (I), or a pharmaceutically acceptable salt or a stereoisomerthereof, wherein:

ring A is 5- to 14-membered heteroaryl, 4- to 14-memberedheterocycloalkyl, C₆₋₁₀ aryl or C₃₋₁₄ cycloalkyl, wherein the 5- to14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each has1-4 heteroatoms as ring members selected from N, O and S, wherein the Nor S atom as ring members is optionally oxidized and one or more carbonatoms as ring members are each optionally replaced by a carbonyl group;and wherein ring A is optionally substituted with 1, 2, 3, 4 or 5 R⁶substituents;

L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, O, —(CR¹⁴R¹⁵)_(q)—,—(CR¹⁴R¹⁵)_(q)—O—, —O(CR¹⁴R¹⁵)_(q)—, —NR¹³—, —(CR¹⁴R¹⁵)_(q)—NR¹³—,—NR¹³—(CR¹⁴R¹⁵)_(q)—, —CH═CH—, —C≡C—, —SO₂NR¹³—, —NR¹³SO₂—,—NR¹³SO₂NR¹³—, —NR¹³C(O)O—, —OC(O)NR¹³— or —NR¹³C(O)NR¹³—;

R³ is methyl, halo, CN or C₁₋₄ haloalkyl;

R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁶ and R¹⁷ are each independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NOH)R^(a), C(═NOH)NR^(a),C(═NCN)NR^(a)R^(a), NR^(a)C(═NCN)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁶ and R¹⁷ are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents;

or two R⁶ substituents attached to the same ring carbon atom takentogether with the ring carbon atom to which they are attached form spiroC₃₋₆ cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each ofwhich is optionally substituted with 1, 2, or 3 independently selectedR^(f) substituents;

each R¹³ is independently H, C₁₋₆ haloalkyl or C₁₋₆ alkyl optionallysubstituted with a substituent selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyland —N(C₁₋₄ alkyl)₂;

R¹⁴ and R¹⁵ are each independently selected from H, halo, CN, OH, —COOH,C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and4-6 membered heterocycloalkyl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl of R¹⁴ or R¹⁵ are eachoptionally substituted with 1, 2, or 3 independently selected R^(q)substituents;

or R¹⁴ and R¹⁵ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5-, 6- or7-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 independently selected R^(q) substituents;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl,5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-14 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 independently selected R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₄ cycloalkyl, 4-14membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),and S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, 5-14 membered heteroaryl, C₃₋₁₄ cycloalkyl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are each optionally substitutedwith 1, 2, or 3 independently selected R^(f) substituents;

each R^(e) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(e) are each optionally substituted with 1, 2 or 3 independentlyselected R^(f) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NOH)R^(c), C(═NOH)NR^(c), C(═NCN)NR^(c)R^(c),NR^(c)C(═NCN)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c); wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(b) are each further optionally substituted with 1, 2 or 3independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(f) substituents;

each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 independently selected R^(n) substituents;

each R^(n) is substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,halo, CN, NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o),C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o),NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o),S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o),and S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(n) are eachoptionally substituted with 1, 2 or 3 independently selected R^(q)substituents;

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1, 2, or 3 independently selected R^(p)substituents;

each R^(p) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(r),OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r),OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) and S(O)₂NR^(r)R^(r), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(p) is optionally substituted with 1,2 or 3 independently selected R^(q) substituents;

or any two R^(a) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3independently selected R^(h) substituents;

each R^(h) is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN,OR^(i), SR^(i), NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i),OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i)NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- ofR^(h) are each further optionally substituted by 1, 2, or 3independently selected R^(j) substituents;

each R^(j) is independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,NHOR^(k), OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k),OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR)NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k), whereinthe C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-memberedheteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy of R^(j) are each optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents;

or two R^(h) groups attached to the same carbon atom of the 4- to10-membered heterocycloalkyl taken together with the carbon atom towhich they are attached form a C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(o) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(r) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

each R^(i), R^(k), R^(o) or R^(r) is independently selected from H, C₁₋₄alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7membered heterocycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₄alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl,C₂₋₄ alkenyl, and C₂₋₄ alkynyl of R^(i), R^(k), R^(o) or R^(r) are eachoptionally substituted with 1, 2 or 3 independently selected R^(q)substituents;

each R^(q) is independently selected from halo, OH, CN, —COOH, NH₂,—NH—C₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, phenyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl and C₃₋₆ cycloalkyl, whereinthe C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl,and 5-6 membered heteroaryl of R^(q) are each optionally substitutedwith 1, 2 or 3 substituents independently selected from halo, OH, CN,—COOH, NH₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,phenyl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl;

the subscript m is an integer of 0, 1, 2 or 3;

the subscript n is an integer of 0, 1, 2 or 3;

each subscript q is independently an integer of 1, 2, 3 or 4; and

the subscript s is an integer of 1, 2, 3 or 4.

In some embodiments, the present disclosure provides, compounds ofFormula (I), or a pharmaceutically acceptable salt or a stereoisomerthereof, wherein:

ring A is 5- to 14-membered heteroaryl, 4- to 14-memberedheterocycloalkyl, C₆₋₁₀ aryl or C₃₋₁₄ cycloalkyl, wherein the 5- to14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each has1-4 heteroatoms as ring members selected from N, O and S, wherein the Nor S atom as ring members is optionally oxidized and one or more carbonatoms as ring members are each optionally replaced by a carbonyl group;and wherein ring A is optionally substituted with 1, 2, 3, 4 or 5 R⁶substituents;

L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, O, —(CR¹⁴R¹⁵)_(q)—,—(CR¹⁴R¹⁵)_(q)—O—, —O(CR¹⁴R¹⁵)_(q)—, —NR¹³—, —(CR¹⁴R¹⁵)_(q)—NR¹³—,—NR¹³—(CR¹⁴R¹⁵)_(q)—, —CH═CH—, —C≡C—, —SO₂NR¹³—, —NR¹³SO₂—,—NR¹³SO₂NR¹³—, —NR¹³C(O)O—, —OC(O)NR¹³— or —NR¹³C(O)NR¹³—;

R³ is methyl, halo, CN or C₁₋₄ haloalkyl;

R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁶ and R¹⁷ are each independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NOH)R^(a), C(═NOH)NR^(a),C(═NCN)NR^(a)R^(a), NR^(a)C(═NCN)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁶ and R¹⁷ are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents;

or two R⁶ substituents attached to the same ring carbon atom takentogether with the ring carbon atom to which they are attached form spiroC₃₋₆ cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each ofwhich is optionally substituted with 1, 2, or 3 independently selectedR^(f) substituents;

each R¹³ is independently H, C₁₋₆ haloalkyl or C₁₋₆ alkyl optionallysubstituted with a substituent selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyland —N(C₁₋₄ alkyl)₂;

R¹⁴ and R¹⁵ are each independently selected from H, halo, CN, OH, —COOH,C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and4-6 membered heterocycloalkyl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl of R¹⁴ or R¹⁵ are eachoptionally substituted with 1, 2, or 3 independently selected R^(q)substituents;

or R¹⁴ and R¹⁵ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5-, 6- or7-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 independently selected R^(q) substituents;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl,5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-14 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 independently selected R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₄ cycloalkyl, 4-14membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),and S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, 5-14 membered heteroaryl, C₃₋₁₄ cycloalkyl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are each optionally substitutedwith 1, 2, or 3 independently selected R^(f) substituents;

each R^(e) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(e) are each optionally substituted with 1, 2 or 3 independentlyselected R^(f) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NOH)R^(c), C(═NOH)NR^(c), C(═NCN)NR^(c)R^(c),NR^(c)C(═NCN)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c); wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(b) are each further optionally substituted with 1, 2 or 3independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(f) substituents;

each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 independently selected R^(n) substituents;

each R^(n) is substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,halo, CN, NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o),C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o),NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o),S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o),and S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(n) are eachoptionally substituted with 1, 2 or 3 independently selected R^(q)substituents;

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1, 2, or 3 independently selected R^(p)substituents;

each R^(p) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(r),OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r),OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) and S(O)₂NR^(r)R^(r), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(p) is optionally substituted with 1,2 or 3 independently selected R^(q) substituents;

or any two R^(a) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3independently selected R^(h) substituents;

each R^(h) is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN,OR^(i), SR^(i), NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i),OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR)NR^(i)R^(i),NR^(i)C(═NR)NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- ofR^(h) are each further optionally substituted by 1, 2, or 3independently selected R^(j) substituents;

each R^(j) is independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, CN,NHOR^(k), OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k),OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k), whereinthe C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-memberedheteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄haloalkyl, and C₁₋₄haloalkoxy of R^(j) are each optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents;

or two R^(h) groups attached to the same carbon atom of the 4- to10-membered heterocycloalkyl taken together with the carbon atom towhich they are attached form a C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(q) substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(q) substituents;

or any two R^(o) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(r) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

each R^(i), R^(k), R^(o) or R^(r) is independently selected from H, C₁₋₄alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7membered heterocycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₄alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl,C₂₋₄ alkenyl, and C₂₋₄ alkynyl of R^(i), R^(k), R^(o) or R^(r) are eachoptionally substituted with 1, 2 or 3 independently selected R^(q)substituents;

each R^(q) is independently selected from halo, OH, CN, —COOH, NH₂,—NH—C₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, phenyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl and C₃₋₆ cycloalkyl, whereinthe C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl,and 5-6 membered heteroaryl of R^(q) are each optionally substitutedwith 1, 2 or 3 substituents independently selected from halo, OH, CN,—COOH, NH₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,phenyl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl;

the subscript m is an integer of 0, 1, 2 or 3;

the subscript n is an integer of 0, 1, 2 or 3;

each subscript q is independently an integer of 1, 2, 3 or 4; and

the subscript s is an integer of 1, 2, 3 or 4.

In some embodiments, the present disclosure provides a compound ofFormula (I), or a pharmaceutically acceptable salt or a stereoisomerthereof, wherein:

ring A is 5- to 14-membered heteroaryl, 4- to 14-memberedheterocycloalkyl, C₆₋₁₀ aryl or C₃₋₁₄ cycloalkyl, wherein the 5- to14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each has1-4 heteroatoms as ring members selected from N, O and S, wherein the Nor S atom as ring members is optionally oxidized and one or more carbonatoms as ring members are each optionally replaced by a carbonyl group;and wherein ring A is optionally substituted with 1, 2, 3, 4 or 5independently selected R⁶ substituents;

L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, O, —(CR¹⁴R¹⁵)_(q)—,—(CR¹⁴R¹⁵)_(q)—O—, —O(CR¹⁴R¹⁵)_(q)—, —NR¹³—, —(CR¹⁴R¹⁵)_(q)—NR¹³—,—NR¹³—(CR¹⁴R¹⁵)_(q)—, —CH═CH—, —C≡C—, —SO₂NR¹³—, —NR¹³SO₂—,—NR¹³SO₂NR¹³—, —NR¹³C(O)O—, —OC(O)NR¹³— or —NR¹³C(O)NR¹³—;

R³ is methyl, halo, CN or C₁₋₄ haloalkyl;

R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁶ and R¹⁷ are each independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NOH)R^(a), C(═NOH)NR^(a),C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), C(═NCN)NR^(a)R^(a),NR^(a)C(═NCN)NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁶ and R¹⁷ are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents;

each R¹³ is independently H, C₁₋₆ haloalkyl or C₁₋₆ alkyl optionallysubstituted with a substituent selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyland —N(C₁₋₄ alkyl)₂;

R¹⁴ and R¹⁵ are each independently selected from H, halo, CN, OH, —COOH,C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and4-6 membered heterocycloalkyl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl of R¹⁴ or R¹⁵ are eachoptionally substituted with 1, 2, or 3 independently selected R^(q)substituents;

or R¹⁴ and R¹⁵ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5-, 6- or7-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 R^(q) substituents;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl,5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-14 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 independently selected R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₄ cycloalkyl, 4-14membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),and S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, 5-14 membered heteroaryl, C₃₋₁₄ cycloalkyl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are each optionally substitutedwith 1, 2, or 3 independently selected R^(q) substituents;

each R^(e) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(e) are each optionally substituted with 1, 2 or 3 independentlyselected R^(q) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NOH)R^(c), C(═NR)NR^(c)R^(c),NR^(c)C(═NR)NR^(c)R^(c), C(═NCN)NR^(c)R^(c), NR^(c)C(═NCN)NR^(c)R^(c),NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) andS(O)₂NR^(c)R^(c); wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(b) are each further optionally substituted with 1, 2 or 3independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(d) substituents;

or any two R^(a) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3independently selected R^(h) substituents;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

each R^(h) is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN,OR^(i), SR^(i), NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i),OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- ofR^(h) are each further optionally substituted by 1, 2, or 3independently selected R^(j) substituents;

each R^(j) is independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,NHOR^(k), OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k),OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR)NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k), whereinthe C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-memberedheteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄haloalkyl, and C₁₋₄haloalkoxy of R^(j) are each optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents;

each of R^(i) and R^(k) is independently selected from H, C₁₋₄ alkyl,C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7 memberedheterocycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₄ alkenyl, andC₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl of R^(i) or R^(k) are each optionally substituted with 1, 2or 3 independently selected R^(q) substituents;

each R^(q) is independently selected from halo, OH, CN, —COOH, NH₂,—NH—C₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, phenyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl and C₃₋₆ cycloalkyl, whereinthe C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl,and 5-6 membered heteroaryl of R^(q) are each optionally substitutedwith 1, 2 or 3 substituents selected from halo, OH, CN, —COOH, NH₂, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl;

the subscript m is an integer of 0, 1, 2 or 3;

the subscript n is an integer of 0, 1, 2 or 3;

each subscript q is independently an integer of 1, 2, 3 or 4; and

the subscript s is an integer of 1, 2, 3 or 4.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or a stereoisomer thereof, wherein:

ring A is 5- to 10-membered heteroaryl, 4- to 11-memberedheterocycloalkyl, C₆₋₁₀ aryl or C₃₋₁₀ cycloalkyl, wherein the 5- to10-membered heteroaryl and 4- to 11-membered heterocycloalkyl each has1-4 heteroatoms as ring members selected from N, O and S, wherein the Nor S atom as ring members is optionally oxidized and one or more carbonatoms as ring members are each optionally replaced by a carbonyl group;and wherein ring A is optionally substituted with 1, 2, 3, 4 or 5 R⁶substituents;

L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, O, —(CR¹⁴R¹⁵)_(q)—,—(CR¹⁴R¹⁵)_(q)—O—, —O(CR¹⁴R¹⁵)_(q)—, —NR¹³—, —(CR¹⁴R¹⁵)_(q)—NR¹³—,—NR¹³—(CR¹⁴R¹⁵)_(q)—, —CH═CH—, —C≡C—, —SO₂NR¹³—, —NR¹³SO₂—, —NR¹³C(O)O—or —NR¹³C(O)NR¹³—;

R³ is methyl, halo, CN or C₁₋₄ haloalkyl;

R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁶ and R¹⁷ are each independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁶ and R¹⁷ are each optionallysubstituted with 1, 2, 3, 4 or 5 R^(b) substituents;

or two R⁶ substituents attached to the same ring carbon atom takentogether with the ring carbon atom to which they are attached form spiroC₃₋₆ cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each ofwhich is optionally substituted with 1, 2, or 3 independently selectedR^(f) substituents;

each R¹³ is independently H, C₁₋₆ haloalkyl or C₁₋₆ alkyl optionallysubstituted with a substituent selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyland —N(C₁₋₄ alkyl)₂;

R¹⁴ and R¹⁵ are each independently selected from H, halo, CN, OH, —COOH,C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and4-6 membered heterocycloalkyl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl of R¹⁴ or R¹⁵ are eachoptionally substituted with 1, 2, or 3 independently selected R^(q)substituents;

or R¹⁴ and R¹⁵ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5- or6-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 R^(q) substituents;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),and S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are each optionally substitutedwith 1, 2, or 3 independently selected R^(f) substituents;

each R^(e) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(e) are each optionally substituted with 1, 2 or 3 independentlyselected R^(f) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c),NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) andS(O)₂NR^(c)R^(c); wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(b) are each further optionally substituted with 1, 2 or 3independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituents;

each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(n) substituents;

each R^(n) is substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,halo, CN, NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o),C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o),NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o),S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o),and S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(n) are eachoptionally substituted with 1, 2 or 3 independently selected R^(q)substituents;

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1, 2, or 3 R^(p) substituents;

each R^(p) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(r),OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r),OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) and S(O)₂NR^(r)R^(r), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(p) is optionally substituted with 1,2 or 3 R^(q) substituents;

or any two R^(a) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3 R^(h)substituents;

each R^(h) is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN,OR^(i), SR^(i), NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i),OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i) S(O)₂R^(i), NR^(i) S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl- ofR^(h) are each further optionally substituted by 1, 2, or 3 R^(j)substituents;

each R^(j) is independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, NHOR^(k), OR^(k),SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k),OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k), whereinthe C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-memberedheteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄haloalkyl, and C₁₋₄haloalkoxy of R^(j) are each optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents;

or two R^(h) groups attached to the same carbon atom of the 4- to10-membered heterocycloalkyl taken together with the carbon atom towhich they are attached form a C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents, or 1, 2 or 3 independently selected R^(q)substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h), or 1, 2 or 3 independently selected R^(q) substituentssubstituents;

or any two R^(o) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(r) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

each R^(i), R^(k), R^(o) or R^(r) is independently selected from H, C₁₋₄alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7membered heterocycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₄alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl,C₂₋₄ alkenyl, and C₂₋₄ alkynyl of R^(i), R^(k), R^(o) or R^(r) are eachoptionally substituted with 1, 2 or 3 R^(q) substituents;

each R^(q) is independently selected from halo, OH, CN, —COOH, NH₂,—NH—C₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, phenyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl and C₃₋₆ cycloalkyl, whereinthe C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl,and 5-6 membered heteroaryl of R^(q) are each optionally substitutedwith 1, 2 or 3 substituents selected from halo, OH, CN, —COOH, NH₂, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl;

the subscript m is an integer of 0, 1, 2 or 3;

the subscript n is an integer of 0, 1, 2 or 3;

each subscript q is independently an integer of 1, 2, 3 or 4; and

the subscript s is an integer of 1, 2, 3 or 4.

In some embodiments, provided herein is a compound of Formula (I): or apharmaceutically acceptable salt or a stereoisomer thereof, wherein:

ring A is 5- to 10-membered heteroaryl, 4- to 11-memberedheterocycloalkyl, C₆₋₁₀ aryl or C₃₋₁₀ cycloalkyl, wherein the 5- to10-membered heteroaryl and 4- to 11-membered heterocycloalkyl each has1-4 heteroatoms as ring members selected from N, O and S, wherein the Nor S atom as ring members is optionally oxidized and one or more carbonatoms as ring members are each optionally replaced by a carbonyl group;and wherein ring A is optionally substituted with 1, 2, 3, 4 or 5 R⁶substituents;

L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, O, —(CR¹⁴R¹⁵)_(q)—,—(CR¹⁴R¹⁵)_(q)—O—, —O(CR¹⁴R¹⁵)_(q)—, —NR¹³—, —(CR¹⁴R¹⁵)_(q)—NR¹³—,—NR¹³—(CR¹⁴R¹⁵)_(q)—, —CH═CH—, —C≡C—, —SO₂NR¹³—, —NR¹³SO₂—, —NR¹³C(O)O—or —NR¹³C(O)NR¹³—;

R³ is methyl, halo, CN or C₁₋₄ haloalkyl;

R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁶ and R¹⁷ are each independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁶ are each optionally substituted with1, 2, 3, 4 or 5 R^(b) substituents;

or two R⁶ substituents attached to the same ring carbon atom takentogether with the ring carbon atom to which they are attached form spiroC₃₋₆ cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each ofwhich is optionally substituted with 1, 2, or 3 independently selectedR^(f) substituents;

each R¹³ is independently H, C₁₋₆ haloalkyl or C₁₋₆ alkyl optionallysubstituted with a substituent selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyland —N(C₁₋₄ alkyl)₂;

R¹⁴ and R¹⁵ are each independently selected from H, halo, CN, OH, —COOH,C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and4-6 membered heterocycloalkyl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl of R¹⁴ or R¹⁵ are eachoptionally substituted with 1, 2, or 3 independently selected R^(q)substituents;

or R¹⁴ and R¹⁵ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5- or6-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 R^(q) substituents;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),and S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are each optionally substitutedwith 1, 2, or 3 independently selected R^(f) substituents;

each R^(e) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(e) are each optionally substituted with 1, 2 or 3 independentlyselected R^(f) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c),NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) andS(O)₂NR^(c)R^(c); wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(b) are each further optionally substituted with 1, 2 or 3independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituents;

each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(n) substituents;

each R^(n) is substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,halo, CN, NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o),C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o),NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o),S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o),and S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(n) are eachoptionally substituted with 1, 2 or 3 independently selected R^(q)substituents;

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1, 2, or 3 R^(p) substituents;

each R^(p) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(r),OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r),OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) and S(O)₂NR^(r)R^(r), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(p) is optionally substituted with 1,2 or 3 R^(q) substituents;

or any two R^(a) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3 R^(h)substituents;

each R^(h) is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN,OR^(i), SR^(i), NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i),OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl- ofR^(h) are each further optionally substituted by 1, 2, or 3 R^(j)substituents;

each R^(j) is independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, NHOR^(k), OR^(k),SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k),OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k), whereinthe C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-memberedheteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy of R^(j) are each optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents;

or two R^(h) groups attached to the same carbon atom of the 4- to10-membered heterocycloalkyl taken together with the carbon atom towhich they are attached form a C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents, or 1, 2 or 3 independently selected R^(q)substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents, or 1, 2 or 3 independently selected R^(q)substituents;

or any two R^(o) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(r) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

each R^(i), R^(k), R^(o) or R^(r) is independently selected from H, C₁₋₄alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7membered heterocycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₄alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl,C₂₋₄ alkenyl, and C₂₋₄ alkynyl of R^(i), R^(k), R^(o) or R^(p) are eachoptionally substituted with 1, 2 or 3 R^(q) substituents;

each R^(q) is independently selected from halo, OH, CN, —COOH, NH₂,—NH—C₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, phenyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl and C₃₋₆ cycloalkyl, whereinthe C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl,and 5-6 membered heteroaryl of R^(q) are each optionally substitutedwith 1, 2 or 3 substituents selected from halo, OH, CN, —COOH, NH₂, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl;

the subscript m is an integer of 0, 1, 2 or 3;

the subscript n is an integer of 0, 1, 2 or 3;

the subscript p is an integer of 1, 2, 3 or 4;

each subscript q is independently an integer of 1, 2, 3 or 4; and

the subscript s is an integer of 1, 2, 3 or 4.

In some embodiments, any two R^(i) substituents together with thenitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(q) substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(q) substituents.

In some embodiments, provided herein is a compound having Formula (I),or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein(1) when L is —C(O)NH—, ring A is not4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl; (2) when L is a bond,ring A not [1,2,4]triazolo[1,5-a]pyridin-2-yl; (3) when L is —NH—, ringA is not 1,7-naphthyridin-8-yl or pyrido[3,2-d]pyrimidin-4-yl; and (4)when L is —C(O)NH—, ring A is not 2-pyridyl.

In some embodiments, provided herein is a compound having Formula (I),or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein(1) when L is —C(O)NH—, ring A is not4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl; (2) when L is a bond,ring A is not [1,2,4]triazolo[1,5-a]pyridin-2-yl; (3) when L is —NH—,ring A is not 1,7-naphthyridin-8-yl or pyrido[3,2-d]pyrimidin-4-yl; or(4) when L is —C(O)NH—, ring A is not 2-pyridyl.

In some embodiments, provided herein is a compound having Formula (Ia):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein:

one of R¹ and R² is —(CR⁸R⁹)_(p)—NR¹⁰R¹¹ and the other is H, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂,—NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂, wherein the C₁₋₄ alkyl and C₁₋₄ alkoxyof R¹ or R² is optionally substituted with 1 or 2 substituentsindependently selected from C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, CN, halo, OH, —COOH, —C(O)NH₂, NH₂, —NHC₁₋₄ alkyl and—N(C₁₋₄ alkyl)₂;

R⁷ is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂, wherein the C₁₋₄alkyl and C₁₋₄ alkoxy are each optionally substituted with 1 or 2substituents independently selected from CN, halo or —C(O)NH₂;

R⁸ and R⁹ are each independently selected from H, halo, CN, OH, —COOH,C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and4-6 membered heterocycloalkyl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl of R⁸ or R⁹ are eachoptionally substituted with 1, 2 or 3 independently selected R^(q)substituents;

or R⁸ and R⁹ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 4-, 5-, 6- or7-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 R^(q) substituents;

or R⁸ and R¹⁰ taken together with the atoms to which they are attachedform 4-, 5-, 6- or 7-membered heterocycloalkyl, having zero to oneadditional heteroatoms as ring members selected from O, N or S, whereinthe 4-, 5-, 6- or 7-membered heterocycloalkyl formed by R⁸ and R¹⁰ areeach optionally substituted with 1 or 2 R^(q) substituents;

R¹⁰ and R¹¹ are each independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₆ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, —C(O)R^(g), —C(O)OR^(g),—C(O)NR^(g)R^(g), —SO₂R^(g) and —SO₂NR^(g)R^(g), wherein the C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₆cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R¹⁰ or R¹¹ are eachoptionally substituted with 1, 2, or 3 independently selected R^(d)substituents;

or R¹⁰ and R¹¹ taken together with the nitrogen atom to which they areattached form 4-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-memberedheterocycloalkyl, wherein the 4-11 membered heterocycloalkyl is eachoptionally substituted with 1, 2 or 3 R^(f) substituents; and R¹² is H,C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH,—COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂. In some embodiments, thesubscript p is 1, 2, 3 or 4.

In some embodiments, provided herein is a compound of Formula (Ia), or apharmaceutically acceptable salt or a stereoisomer thereof, wherein:

one of R¹ and R² is —(CR⁸R⁹)_(p)—NR¹⁰R¹¹ and the other is H, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂,—NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂, wherein the C₁₋₄ alkyl and C₁₋₄ alkoxyof R¹ or R² is optionally substituted with 1 or 2 substituentsindependently selected from C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, CN, halo, OH, —COOH, —C(O)NH₂, NH₂, —NHC₁₋₄ alkyl and—N(C₁₋₄ alkyl)₂;

R⁷ is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂, wherein the C₁₋₄alkyl and C₁₋₄ alkoxy are each optionally substituted with 1 or 2substituents independently selected from CN, halo or —C(O)NH₂;

R⁸ and R⁹ are each independently selected from H, halo, CN, OH, —COOH,C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and4-6 membered heterocycloalkyl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl of R⁸ or R⁹ are eachoptionally substituted with 1, 2 or 3 independently selected R^(q)substituents;

or R⁸ and R⁹ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 4-, 5-, 6- or7-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 R^(q) substituents;

or R⁸ and R¹⁰ taken together with the atoms to which they are attachedform 4-, 5-, 6- or 7-membered heterocycloalkyl, having zero to oneadditional heteroatoms as ring members selected from O, N or S, whereinthe 4-, 5-, 6- or 7-membered heterocycloalkyl formed by R⁸ and R¹⁰ areeach optionally substituted with 1 or 2 R^(q) substituents;

R¹⁰ and R¹¹ are each independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₆ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, —C(O)R^(g), —C(O)OR^(g),—C(O)NR^(g)R^(g), —SO₂R^(g) and —SO₂NR^(g)R^(g), wherein the C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₆cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R¹⁰ or R¹¹ are eachoptionally substituted with 1, 2, or 3 independently selected R^(d)substituents;

or R¹⁰ and R¹¹ taken together with the nitrogen atom to which they areattached form 4-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-memberedheterocycloalkyl, wherein the 4-11 membered heterocycloalkyl is eachoptionally substituted with 1, 2 or 3 R^(f) substituents;

R¹² is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂; and

the subscript p is an integer of 1, 2, 3 or 4

In some embodiments, provided herein is a compound having Formula (II):

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In some embodiments, provided herein is a compound having Formula (IIa):

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In some embodiments, provided herein is a compound having Formula (IIb):

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In some embodiments, provided herein is a compound having Formula(IIb-1):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein:

ring A is 5- to 10-membered heteroaryl, 4- to 11-memberedheterocycloalkyl or C₆₋₁₀ aryl, wherein the 5- to 10-membered heteroaryland 4- to 11-membered heterocycloalkyl each has 1-4 heteroatoms as ringmembers selected from N, O and S, wherein the N or S atom as ringmembers is optionally oxidized and one or more carbon atoms as ringmembers are each optionally replaced by a carbonyl group; and whereinring A is optionally substituted with 1, 2 or 3 R⁶ substituents; and

L is a bond, —C(O)NH—, —NH— or —OCH₂—, wherein the carbonyl group in the—C(O)NH— linkage or the oxygen atom in the —OCH₂— linkage is attached toring A.

In some embodiments, provided herein is a compound having Formula (IIc):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein:

X¹, X², X³, X⁴, X⁵ and X⁶ are each independently N or CH, with theproviso that X¹, X⁵ and X⁶ are not simultaneously N;

R¹³ is H or C₁₋₄ alkyl; and

the subscript r is an integer of 1, 2 or 3.

In some embodiments, provided herein is a compound having Formula(IIc-1):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or 3.

In some embodiments, provided herein is a compound having Formula(IIc-2):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or 3.

In some embodiments, provided herein is a compound having Formula(IIc-3):

or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein

R¹³ is H or C₁₋₄ alkyl; and

the subscript r is an integer of 1, 2 or 3.

In some embodiments, provided herein is a compound having Formula(IIc-4):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or 3.

In some embodiments, provided herein is a compound having Formula (IId):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein:

R¹³ is H or C₁₋₄ alkyl;

R¹⁸ is H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R¹⁸ are each optionallysubstituted with 1, 2, or 3 R^(b) substituents; and

the subscript t is an integer of 0, 1 or 2.

In some embodiments, R¹³ is H.

In some embodiments, provided herein is a compound having Formula (IIe):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or 3.

In some embodiments, provided herein is a compound having Formula (IIf):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or 3.

In some embodiments, provided herein is a compound having Formula(IIf-1):

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In some embodiments, provided herein is a compound having Formula (IIg):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript t is an integer of 0, 1 or 2.

In some embodiments, provided herein is a compound having Formula (IIh):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or 3.

In some embodiments, provided herein is a compound having Formula (IIj):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or 3.

In some embodiments, provided herein is a compound having Formula (IIk):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or 3.

In some embodiments, provided herein is a compound having Formula (IIm):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or 3.

In some embodiments, provided herein is a compound having Formula (IIn):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or 3.

In some embodiments, provided herein is a compound having Formula (IIo):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or 3.

In some embodiments, provided herein is a compound having Formula (IIp):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or 3.

In some embodiments, provided herein is a compound having Formula (III):

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In some embodiments, provided herein is a compound having Formula(IIIa):

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In some embodiments, provided herein is a compound having Formula(IIIb):

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In some embodiments, provided herein are compounds having Formula (IV):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is 1, 2, 3, 4 or 5.

In one embodiment, ring A is pyridyl, for example, 2-pyridyl. In someembodiments, the subscript n is 0, 1 or 2 and each R⁵ is independentlyC₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH,—COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂. In certain instances, R⁵is halo or C₁₋₄ alkyl. In some embodiments, the subscript m is 0. Insome embodiments, the subscript r is 1 or 2. In some embodiments, R¹² isH, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo,—COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂. In one embodiment, R² isH. In some embodiments, the subscript p is 1 and R⁸ and R⁹ are each H.In one embodiment, R¹⁰ is H. In some embodiments, R⁸ and R¹⁰ takentogether form 4- to 6-membered heterocycloalkyl, optionally substitutedwith 1 or 2 R^(q) substituents. In some embodiments, R¹⁰ and R¹¹ takentogether form 4- to 6-membered heterocycloalkyl, optionally substitutedwith 1 or 2 R^(q) substituents.

In some embodiments, provided herein are compounds having Formula (V):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is 1, 2, 3, 4 or 5, the other variables of Formula (V)are as defined in any embodiment disclosed herein. In some embodiments,the subscript r is 1 or 2.

In some embodiments, provided herein are compounds having Formula (VI):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is 1, 2, 3, 4 or 5, the other variables of Formula (VI)are as defined in any embodiment disclosed herein. In some embodiments,the subscript r is 1 or 2.

In some embodiments, provided herein are compounds having Formula (VIIa)or (VIIb):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is 1, 2, 3, 4 or 5, the other variables of Formula(VIIa) or (VIIb) are as defined in any embodiment disclosed herein. Insome embodiments, the subscript r is 1 or 2.

In some embodiments, provided herein are compounds having Formula(VIIIa) or (VIIIb):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is 1, 2, 3, 4 or 5, the other variables of Formula(VIIIa) or (VIIIb) are as defined in any embodiment disclosed herein. Insome embodiments, the subscript r is 1 or 2.

In some embodiments, ring A is 5- to 14-membered heteroaryl, 4- to14-membered heterocycloalkyl, or C₆₋₁₀ aryl, wherein the 5- to14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each has1-4 heteroatoms as ring members selected from N, O and S, wherein the Nor S atom as ring members is optionally oxidized and one or more carbonatoms as ring members are each optionally replaced by a carbonyl group;and wherein ring A is optionally substituted with 1, 2, or 3 R⁶substituents. In some embodiments, ring A is 5- to 14-memberedheteroaryl or 4- to 14-membered heterocycloalkyl, wherein the 5- to14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each has1-4 heteroatoms as ring members selected from N, O and S, wherein the Nor S atom as ring members is optionally oxidized and one or more carbonatoms as ring members are each optionally replaced by a carbonyl group;and wherein ring A is optionally substituted with 1, 2, or 3 R⁶substituents. In some embodiments, ring A is 5- to 14-memberedheteroaryl, wherein the 5- to 14-membered heteroaryl has 1-4 heteroatomsas ring members selected from N, O and S, wherein the N or S atom asring members is optionally oxidized and one or more carbon atoms as ringmembers are each optionally replaced by a carbonyl group; and whereinring A is optionally substituted with 1, 2, or 3 R⁶ substituents. Insome embodiments, ring A is 4- to 14-membered heterocycloalkyl, whereinthe 4- to 14-membered heterocycloalkyl each has 1-4 heteroatoms as ringmembers selected from N, O and S, wherein the N or S atom as ringmembers is optionally oxidized and one or more carbon atoms as ringmembers are each optionally replaced by a carbonyl group; and whereinring A is optionally substituted with 1, 2, or 3 R⁶ substituents. Insome embodiments, ring A is C₆₋₁₀ aryl is optionally substituted with 1,2, or 3 R⁶ substituents.

In some embodiments, ring A is selected from:

wherein each subscript r is an integer of 1, 2, 3, 4 or 5; R¹⁶ is C₁₋₆alkyl; and the wavy line indicates the point of attachment to L.

In some embodiments, ring A is selected from:

wherein each subscript r is an integer of 1, 2, 3, 4 or 5; and the wavyline indicates the point of attachment to L.

In some embodiments, ring A is selected from:

wherein each subscript r is an integer of 1, 2, 3, 4 or 5; and the wavyline indicates the point of attachment to L.

In some embodiments, ring A is selected from:

wherein each subscript r is an integer of 1, 2, 3, 4 or 5; and the wavyline indicates the point of attachment to L.

In some embodiments, ring A is selected from:

wherein each subscript r is an integer of 1, 2, 3, 4 or 5; and the wavyline indicates the point of attachment to L.

In some embodiments, ring A is selected from:

wherein each subscript r is an integer of 1, 2, 3, 4 or 5; R¹⁶ is C₁₋₆alkyl; and the wavy line indicates the point of attachment to L.

In some embodiments, ring A is selected from:

wherein each subscript r is an integer of 1, 2, 3, 4 or 5; and the wavyline indicates the point of attachment to L.

In some embodiments, ring A is selected from:

wherein each subscript r is an integer of 1, 2, 3, 4 or 5; and the wavyline indicates the point of attachment to L.

In some embodiments, ring A is selected from:

wherein each subscript r is an integer of 1, 2, 3, 4 or 5; and the wavyline indicates the point of attachment to L.

In some embodiments, ring A is selected from:

wherein each subscript r is an integer of 1, 2, 3, 4 or 5; and the wavyline indicates the point of attachment to L.

In some embodiments, ring A is selected from:

wherein the subscript r is an integer of 1, 2, 3, 4 or 5, and the wavyline indicates the point of attachment to L.

In some embodiments, ring A is selected from:

wherein the subscript r is an integer of 1, 2, 3, 4 or 5, and the wavyline indicates the point of attachment to L.

In some embodiments, ring A is 2-pyridyl, optionally substituted with 1,2, 3, or 4 independently selected R⁶ substituents.

In some embodiments, ring A is selected from:

wherein the subscript r is an integer of 1, 2 or 3.

In some embodiments, ring A is selected from:

wherein the subscript r is an integer of 1, 2 or 3.

In some embodiments, L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, O,—(CR¹⁴R¹⁵)_(q)—, —(CR¹⁴R¹⁵)_(q)—O—, —O(CR¹⁴R¹⁵)_(q)—, —NR¹³—,—(CR¹⁴R¹⁵)_(q)—NR¹³—, or —NR¹³—(CR¹⁴R¹⁵)_(q)—, wherein the subscript qis 1, 2 or 3. In some embodiments, L is a bond, —C(O)NR¹³—, —NR¹³C(O)—,—(CR¹⁴R¹⁵)_(q)—O—, —O(CR¹⁴R¹⁵)_(q)—, or —NR¹³—, wherein the subscript qis 1, 2 or 3.

In some embodiments, L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, or —NR¹³—. Insome embodiments, L is a bond, —C(O)NR¹³—, or —NR¹³—.

In some embodiments, L is a bond, —NH—, —CH═CH— or —C(O)NH—, wherein thecarbonyl group in the —C(O)NH— linkage is attached to ring A.

In some embodiments, L is a bond, —NR¹³—, —(CR¹⁴R¹⁵)_(q)O—,—O(CR¹⁴R¹⁵)_(q)—, —(CR¹⁴R¹⁵)_(q)NR¹³— or —NR¹³—(CR¹⁴R¹⁵)_(q)—, whereinthe subscript q is 1, 2 or 3. In certain instances, R¹⁴ and R¹⁵ are eachindependently H or C₁₋₄ alkyl. In other instances, R¹⁴ and R¹⁵ takentogether form C₃₋₆ cycloalkyl or 4-6-membered heterocycloalkyl, each ofwhich is optionally substituted with 1 or 2 R^(q) substituents.

In some embodiments, L is a bond.

In some embodiments, L is —NR¹³—. In certain instances, R¹³ is H or C₁₋₄alkyl.

In some embodiments, L is —CH₂O— or —OCH₂—.

In some embodiments, L is —NR¹³CH₂— or —CH₂NR¹³. In certain instances,R¹³ is H or C₁₋₄ alkyl.

In some embodiments, L is —C(O)NH—. In some embodiments, L is —NH—.

In some embodiments, the subscript m is an integer of 0 or 1. In someembodiments, the subscript m is 0.

In some embodiments, R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, CN, halo, or OH. In some embodiments, R⁵ is C₁₋₄ alkyl, C₁₋₄alkoxy, halo, or OH. In some embodiments, R⁵ is C₁₋₄ alkyl or halo. Insome embodiments, R⁵ is C₁₋₄ alkyl. In some embodiments, R⁵ is halo. Insome embodiments, the subscript n is 1 and R⁵ is halo or C₁₋₄ alkyl.

In some embodiments, R³ is methyl, halo, or CN. In some embodiments, R³is methyl, CN or Cl. In some embodiments, R³ is methyl. In someembodiments, R³ is CN. In some embodiments, R³ is Cl.

In some embodiments, R³ and R⁵ are each independently halo, methyl orCN.

In some embodiments, R⁷ is CN or halo.

In some embodiments, R¹² is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, CN, halo, or OH, wherein the C₁₋₄ alkyl and C₁₋₄ alkoxyof R¹² are each optionally substituted with phenyl, C₃₋₆ cycloalkyl,5-6-membered heteroaryl or 4-6-membered heterocycloalkyl. In someembodiments, R¹² is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, or halo. In someembodiments, R¹² is H, halo, CN, C₁₋₄ alkyl or C₁₋₄ alkoxy. In someembodiments, R¹² is H or C₁₋₄ alkyl. In some embodiments, R¹² is H.

In some embodiments, R⁶ and R¹⁷ are each independently selected from H,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), and NR^(a)C(O)OR^(a), wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl,5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl- and (4-14 membered heterocycloalkyl)-C₁₋₄ alkyl-of R⁶ and R¹⁷ are each optionally substituted with 1, 2, 3, 4 or 5independently selected R^(b) substituents.

In some embodiments, R⁶ and R¹⁷ are each independently selected from H,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OR^(a), C(O)R^(a), C(O)NR^(a)R^(a),C(O)OR^(a), NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), and NR^(a)C(O)OR^(a),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₄cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl- and (4-14 membered heterocycloalkyl)-C₁₋₄ alkyl-of R⁶ and R¹⁷ are each optionally substituted with 1, 2, or 3independently selected R^(b) substituents.

In some embodiments, R⁶ and R¹⁷ are each independently selected from H,halo, C₁₋₆ alkyl, 4-14 membered heterocycloalkyl, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OR^(a), and C(O)R^(a), wherein theC₁₋₆ alkyl, 4-14 membered heterocycloalkyl, and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁶ and R¹⁷ are each optionallysubstituted with 1 or 2 independently selected R^(b) substituents.

In some embodiments, R⁶ is H, C₁₋₆ alkyl, 2-hydroxyethyl,1-(2-hydroxyethyl)azetidin-3-yl, pyrrolidin-2-yl,3-(dimethylamino)propanoyl, 1-methylpyrrolidine-2-carbonyl,2-(4-methylpiperazin-1-yl)acetyl, 2-(isopropylamino)acetyl,2-((R)-3-hydroxypyrrolidin-1-yl)acetyl,2-((S)-3-hydroxypyrrolidin-1-yl)acetyl,2-(3-hydroxypyrrolidin-1-yl)acetyl, 2-(azetidin-1-yl)acetyl,2-(ethyl(methyl)amino)acetyl,2-((S)-3-hydroxy-3-methylpyrrolidin-1-yl)acetyl,2-((R)-3-hydroxy-3-methylpyrrolidin-1-yl)acetyl,(S)-(1-methylpyrrolidin-2-yl)methanoyl,2-(3-hydroxyazetidin-1-yl)acetyl, 2-((R)-3-hydroxyazetidin-1-yl)acetyl,2-((S)-3-hydroxyazetidin-1-yl)acetyl,2-(3-hydroxy-3-methylazetidin-1-yl)acetyl,2-((R)-3-hydroxy-3-methylazetidin-1-yl)acetyl,2-((S)-3-hydroxy-3-methylazetidin-1-yl)acetyl, 2-(azetidin-1-yl)acetyl,pyrrolidin-1-ylmethyl, azetidin-1-ylmethyl,3-hydroxyazetidin-1-yl)methyl, (R)-3-hydroxyazetidin-1-yl)methyl,(S)-3-hydroxyazetidin-1-yl)methyl,2-(3-hydroxy-3-methylpyrrolidin-1-yl)methyl,2-((S)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl,2-((R)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl,1-((R)-3-hydroxypyrrolidin-1-yl)ethyl,(((S)-2-hydroxypropyl)amino)methyl, (((R)-2-hydroxypropyl)amino)methyl,((-2-hydroxypropyl)amino)methyl, (2-hydroxyethyl)amino)methyl,(3-carboxypyrrolidin-1-yl)methyl, (R)-(3-carboxypyrrolidin-1-yl)methyl,(S)-(3-carboxypyrrolidin-1-yl)methyl, (3-hydroxypyrrolidin-1-yl)methyl,(R)-(3-hydroxypyrrolidin-1-yl)methyl,(S)-(3-hydroxypyrrolidin-1-yl)methyl, (2-hydroxyethylamino)methyl,(2-hydroxy-2-methylpropylamino)methyl, 2-(dimethylamino)ethanoyl,2-(3-carboxyazetidin-1-yl)ethanoyl,(R)-2-(3-carboxyazetidin-1-yl)ethanoyl,(S)-2-(3-carboxyazetidin-1-yl)ethanoyl,2-(2-carboxypiperidin-1-yl)ethanoyl,(R)-2-(2-carboxypiperidin-1-yl)ethanoyl,(S)-2-(2-carboxypiperidin-1-yl)ethanoyl,2-(3-carboxypyrrolidin-1-yl)ethanoyl,(S)-2-(3-carboxypyrrolidin-1-yl)ethanoyl,(R)-2-(3-carboxypyrrolidin-1-yl)ethanoyl, (5-cyanopyridin-3-yl)methoxy,halo or CN.

In some embodiments, R⁶ is 2-(3-hydroxypyrrolidin-1-yl)ethyl,(R)-2-(3-hydroxypyrrolidin-1-yl)ethyl,(S)-2-(3-hydroxypyrrolidin-1-yl)ethyl, 4,5-dihydro-1H-imidazol-2-yl,(S)-(1-hydroxybutan-2-ylamino)methyl,(S)-(1-hydroxybutan-2-ylamino)methyl, (1-hydroxybutan-2-ylamino)methyl,(S)-(1-hydroxypropan-2-ylamino)methyl,(R)-(1-hydroxypropan-2-ylamino)methyl,(1-hydroxypropan-2-ylamino)methyl, (methylamino)methyl,(1-hydroxy-2-methylpropan-2-ylamino)methyl,(1-hydroxycyclopropyl)methylamino)methyl,(4-carboxypiperidin-1-yl)methyl,(R)-(3-carboxy-3-methylpyrrolidin-1-yl)methyl,(S)-(3-carboxy-3-methylpyrrolidin-1-yl)methyl,(3-carboxy-3-methylpyrrolidin-1-yl)methyl,2-(isopropyl(methyl)amino)acetyl, 2-(ethyl(methyl)amino)acetyl,2-((cyclopropylmethyl)(methyl)amino)acetyl,2-(4-ethylpiperazin-1-yl)acetyl, 2-(4-methylpiperazin-1-yl)acetyl,2-((2-hydroxyethyl)(methyl)amino)acetyl,2-(((R)-1-hydroxypropan-2-yl)(methyl)amino)acetyl,2-(((S)-1-hydroxypropan-2-yl)(methyl)amino)acetyl,2-((-1-hydroxypropan-2-yl)(methyl)amino)acetyl, (4-boronophenyl)methyl,2-(methyl(methyl)amino)acetyl, 2-(4-hydroxypiperidin-1-yl)acetyl,2-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)acetyl,(4-carboxycyclohexyl)methyl, trans-(4-carboxycyclohexyl)methyl,cis-(4-carboxycyclohexyl)methyl,(3-carboxybicyclo[1.1.1]pentan-1-yl)methyl,3-carboxy-3-methylcyclobutyl, 4-carboxycycloheptanyl,2-(4-carboxycyclohexan-1-yl)ethyl, (4-carboxycyclohexan-1-yl)methyl,(4-carboxybicyclo[2.2.1]heptan-1-yl)methyl or(4-carboxy-4-methylcyclohexyl)methyl.

In some embodiments, R⁷ H, is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, CN, halo, or OH, wherein the C₁₋₄ alkyl and C₁₋₄ alkoxyare each optionally substituted with 1 or 2 substituents independentlyselected from CN, halo or —C(O)NH₂. In some embodiments, R⁷ is H, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, or halo,wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy are each optionally substitutedwith 1 or 2 substituents independently selected from CN or halo. In someembodiments, R⁷ is H, halo, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy or C₁₋₄haloalkoxy, wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy of R⁷ are eachoptionally substituted with CN. In some embodiments, R⁷ is H, halo, CN,C₁₋₄ alkyl, C₁₋₄ alkoxy or C₁₋₄ haloalkoxy. In some embodiments, R⁷ ishalo. In some embodiments, R⁷ is H.

In some embodiments, one of R¹ and R² is —(CR⁸R⁹)_(p)—NR¹⁰R¹¹ and theother is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,CN, halo, or OH, wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy of R¹ or R² isoptionally substituted with 1 or 2 substituents independently selectedfrom C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, and OH. Insome embodiments, one of R¹ and R² is —(CR⁸R⁹)_(p)—NR¹⁰R¹¹ and the otheris H, C₁₋₄ alkyl or C₁₋₄ alkoxy, wherein the C₁₋₄ alkyl and C₁₋₄ alkoxyof R¹ or R² is optionally substituted with 1 or 2 substituentsindependently selected from C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, and CN.

In some embodiments, R² is cyanomethoxy.

In some embodiments, R¹ is cyanomethoxy.

In some embodiments, the subscript p is 1, 2, or 3. In some embodiments,the subscript p is 1 or 2. In some embodiments, the subscript p is 1.

In some embodiments, R⁸ and R⁹ are each independently selected from H,halo, CN, OH, —COOH, C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄alkyl)₂, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy. In some embodiments, R⁸and R⁹ are each independently selected from H, halo, CN, OH, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy. In some embodiments,R⁸ and R⁹ are each independently selected from H, halo, C₁₋₄ alkyl andC₁₋₄ alkoxy. In some embodiments, R⁸ is H. In some embodiments, R⁹ is H.In some embodiments, R⁸ and R⁹ are each H.

In some embodiments, R¹⁰ is selected from H, C₁₋₆ alkyl, and C₁₋₆haloalkyl. In some embodiments, R¹⁰ is selected from H and C₁₋₆ alkyl.In some embodiments, R¹⁰ is H.

In some embodiments, R¹¹ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,—C(O)R^(g), —C(O)OR^(g), —C(O)NR^(g)R^(g), —SO₂R^(g) and—SO₂NR^(g)R^(g), wherein the C₁₋₆ alkyl and C₁₋₆ haloalkyl of R¹¹ areeach optionally substituted with 1 or 2 independently selected R^(f)substituents. In some embodiments, R¹¹ is selected from H and C₁₋₆ alkyloptionally substituted with 1 or 2 independently selected R^(f)substituents. In some embodiments, R¹¹ is 2-hydroxyethyl,2-carboxyethyl, [1-(hydroxymethyl)cyclopropyl]methyl,[1-(hydroxymethyl)cyclobutyl]methyl or 2-(dimethylamino)-2-oxo-ethyl.

In some embodiments, —NR¹⁰R¹¹ is (2-hydroxyethyl)amino,(2-carboxyethyl)amino, 2-carboxy-1-piperidinyl, 2-oxooxazolidin-3-yl,[1-(hydroxymethyl)cyclopropyl]methylamino,[1-(hydroxymethyl)cyclobutyl]methylamino, 3-carboxypyrrolidin-1-yl,(R)-3-carboxypyrrolidin-1-yl, (S)-3-carboxypyrrolidin-1-yl,(S)-2-carboxypyrrolidin-1-yl, (R)-2-carboxypyrrolidin-1-yl,2-carboxypyrrolidin-1-yl, (1-carboxyethyl)amino,(R)-(1-carboxyethyl)amino, (S)-(1-carboxyethyl)amino,3-methyl-3-carboxypyrrolidin-1-yl, 4-carboxypiperidin-1-yl,(S)-4-carboxypiperidin-1-yl, (R)-4-carboxypiperidin-1-yl,3-carboxy-azetidin-1-yl, (R)-3-carboxy-azetidin-1-yl,(S)-3-carboxy-azetidin-1-yl, (2-hydroxyethyl)(methyl)amino,[2-(dimethylamino)-2-oxo-ethyl]amino,(R)-3-methyl-3-carboxypyrrolidin-1-yl,(S)-3-methyl-3-carboxypyrrolidin-1-yl, (1-carboxyethyl)amino,(4-carboxycyclohexyl)amino, 3-(methylaminocarbonyl)pyrrolidin-1-yl,(R)-3-(methylaminocarbonyl)pyrrolidin-1-yl,(S)-3-(methylaminocarbonyl)pyrrolidin-1-yl,3-(2-hydroxyethylaminocarbonyl)pyrrolidin-1-yl,(R)-3-(2-hydroxyethylaminocarbonyl)pyrrolidin-1-yl,(S)-3-(2-hydroxyethylaminocarbonyl)pyrrolidin-1-yl,2-(methylcarbonylamino)ethylamino,3-(2-hydroxyethylcarbonylamino)pyrrolidin-1-yl,(R)-3-(2-hydroxyethylcarbonylamino)pyrrolidin-1-yl,(S)-3-(2-hydroxyethylcarbonylamino)pyrrolidin-1-yl,(R)-3-hydroxypyrrolidin-1-yl, (S)-3-hydroxypyrrolidin-1-yl, or3-hydroxypyrrolidin-1-yl

In some embodiments, —NR¹⁰R¹¹ is (2-hydroxyethyl)amino,(2-carboxyethyl)amino, 2-carboxy-1-piperidinyl, 2-oxooxazolidin-3-yl,[1-(hydroxymethyl)cyclopropyl]methylamino,[1-(hydroxymethyl)cyclobutyl]methylamino, 3-carboxypyrrolidin-1-yl,(S)-2-carboxypyrrolidin-1-yl, (S)-3-methyl-3-carboxypyrrolidin-1-yl,4-carboxypiperidin-1-yl, 3-carboxy-azetidin-1-yl,(2-hydroxyethyl)(methyl)amino, [2-(dimethylamino)-2-oxo-ethyl]amino,(R)-3-methyl-3-carboxypyrrolidin-1-yl, (1-carboxyethyl)amino,(4-carboxycyclohexyl)amino, 3-(methylaminocarbonyl)pyrrolidin-1-yl,3-(2-hydroxyethylaminocarbonyl)pyrrolidin-1-yl,2-(methylcarbonylamino)ethylamino,3-(2-hydroxyethylcarbonylamino)pyrrolidin-1-yl, or3-hydroxypyrrolidin-1-yl.

In some embodiments, —NR¹⁰R¹¹ is (2-hydroxyethyl)amino,(2-carboxyethyl)amino, 2-carboxy-1-piperidinyl, 2-oxooxazolidin-3-yl,[1-(hydroxymethyl)cyclopropyl]methylamino,[1-(hydroxymethyl)cyclobutyl]methylamino, 3-carboxypyrrolidin-1-yl,(S)-2-carboxypyrrolidin-1-yl, (S)-3-methyl-3-carboxypyrrolidin-1-yl,4-carboxypiperidin-1-yl, 3-carboxy-azetidin-1-yl,(2-hydroxyethyl)(methyl)amino or [2-(dimethylamino)-2-oxo-ethyl]amino.

In some embodiments, —NR¹⁰R¹¹ is (2-hydroxyethyl)amino,(2-carboxyethyl)amino, 2-carboxy-1-piperidinyl, 2-oxooxazolidin-3-yl,[1-(hydroxymethyl)cyclopropyl]methylamino,[1-(hydroxymethyl)cyclobutyl]methylamino or[2-(dimethylamino)-2-oxo-ethyl]amino.

In some embodiments, —NR¹⁰R¹¹ is5-carboxy-2-azabicyclo[2.2.1]heptan-2-yl,4-carboxy-2-azbicyclo[2.1.1]hexan-2-yl,6-carboxy-2-azaspiro[3.3]heptan-2-yl,3-carboxy-3-methoxymethylpyrrolidin-1-yl,(R)-3-carboxy-3-methoxymethylpyrrolidin-1-yl,(S)-3-carboxy-3-methoxymethylpyrrolidin-1-yl,4-carboxy-2-azabicyclo[2.1.1]hexan-2-yl,3-methanesulfamoylpyrrolidin-1-yl,5-carboxy-2-azabicyclo[2.2.1]heptan-2-yl,5-hydroxy-2-azabicyclo[2.2.1]heptan-2-yl, pyrrolidin-1-yl, (1R,3S)-3-carboxycyclopentan-1-ylamino, (1R,3R)-3-carboxycyclopentan-1-ylamino, (1S,3S)-3-carboxycyclopentan-1-ylamino, (1S,3R)-3-carboxycyclopentan-1-ylamino, (1R,2R)-2-carboxycyclopentan-1-ylamino, (1S,2S)-2-carboxycyclopentan-1-ylamino, (1R,2S)-2-carboxycyclopentan-1-ylamino, (1S,2R)-2-carboxycyclopentan-1-ylamino, trans-3-carboxycyclobutan-1-ylamino,cis-3-carboxycyclobutan-1-ylamino,trans-4-(carboxymethyl)cyclohexan-1-ylamino,cis-4-(carboxymethyl)cyclohexan-1-ylamino,4-carboxybicyclo[2.2.1]heptan-1-ylamino, (R)-2-hydroxypropylamino,(S)-2-hydroxypropylamino, (R)-3-hydroxy-propan-2-ylamino or(S)-3-hydroxy-propan-2-ylamino.

In some embodiments, R¹⁴ and R¹⁵ are each independently selected from H,halo, CN, OH, —COOH, C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄alkyl)₂, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy. In some embodiments, R¹⁴and R¹⁵ are each independently selected from H, halo, CN, OH, —COOH, andC₁₋₄ alkyl. In some embodiments, R¹⁴ and R¹⁵ are each independentlyselected from H and C₁₋₄ alkyl. In some embodiments, R¹⁴ and R¹⁵ are H.

In some embodiments, each R^(a) is independently selected from H, CN,C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5-14 memberedheteroaryl, 4-14 membered heterocycloalkyl, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-14 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5-14membered heteroaryl, 4-14 membered heterocycloalkyl, (5-14 memberedheteroaryl)-C₁₋₄ alkyl- and (4-14 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(a) are each optionally substituted with 1, 2, or 3 independentlyselected R^(d) substituents. In some embodiments, each R^(a) isindependently selected from H, C₁₋₆ alkyl, 4-14 memberedheterocycloalkyl, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-14membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, 4-14membered heterocycloalkyl, (5-14 membered heteroaryl)-C₁₋₄ alkyl- and(4-14 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are eachoptionally substituted with 1 or 2 independently selected R^(d)substituents.

In some embodiments, each R^(d) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, halo, 5-10 membered heteroaryl, 4-14 memberedheterocycloalkyl, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, OR^(e), C(O)R^(e),C(O)NR^(e)R^(e), C(O)OR^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), and NR^(e)C(O)OR^(e), wherein the C₁₋₆ alkyl,C₁₋₆ haloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-14membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are each optionallysubstituted with 1, 2, or 3 independently selected R^(f) substituents.In some embodiments, each R^(d) is independently selected from C₁₋₆alkyl, 4-14 membered heterocycloalkyl, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, OR^(e), C(O)OR^(e), NHR^(e), andNR^(e)R^(e), wherein the C₁₋₆ alkyl, 4-14 membered heterocycloalkyl, and(4-14 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are eachoptionally substituted with 1, 2, or 3 independently selected R^(f)substituents.

In some embodiments, each R^(e) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl. In someembodiments, each R^(e) is independently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(b) substituent is independently selectedfrom halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, CN, OH, NH₂, OR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), and NR^(c)C(O)OR^(c); wherein theC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆alkynyl of R^(b) are each further optionally substituted with 1, 2 or 3independently selected R^(d) substituents. In some embodiments, eachR^(b) substituent is independently selected from halo, C₁₋₆ alkyl, OH,NH₂, OR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), NHR^(c), andNR^(c)R^(c); wherein the C₁₋₆ alkyl of R^(b) is further optionallysubstituted with 1 or 2 independently selected R^(d) substituents. Insome embodiments, each R^(b) substituent is independently selected fromC₁₋₆ alkyl, OH, NH₂, OR^(c), C(O)NR^(c)R^(c), C(O)OR^(c), NHR^(c), andNR^(c)R^(c); wherein the C₁₋₆ alkyl of R^(b) is further optionallysubstituted with 1 or 2 independently selected R^(d) substituents.

In some embodiments, each R^(c) is independently selected from H, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, and4-10 membered heterocycloalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl ofR^(c) are each optionally substituted with 1, 2, or 3 independentlyselected R^(f) substituents. In some embodiments, each R^(c) isindependently selected from H, C₁₋₆ alkyl, and C₃₋₁₀ cycloalkyl, whereinthe C₁₋₆ alkyl and C₃₋₁₀ cycloalkyl of R^(c) are each optionallysubstituted with 1 or 2 independently selected R^(f) substituents.

In some embodiments, each R^(f) is independently selected from C₁₋₄alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(g),C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), NHR^(g), NR^(g)R^(g), andNR^(g)C(O)R^(g). In some embodiments, each R^(f) is independentlyselected from C₁₋₄ alkyl, OR^(g), C(O)OR^(g), and NR^(g)C(O)R^(g). Insome embodiments, each R^(g) is independently selected from H, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl. In someembodiments, each R^(g) is independently selected from H and C₁₋₆ alkyl.

In some embodiments, the subscript m is an integer of 0, 1, or 2. Insome embodiments, the subscript m is an integer of 0 or 1. In someembodiments, the subscript m is an integer of 0.

In some embodiments, the subscript n is an integer of 0, 1 or 2. In someembodiments, the subscript n is an integer of 0 or 1. In someembodiments, the subscript n is an integer of 0. In some embodiments,the subscript n is an integer of 1.

In some embodiments, each subscript q is independently an integer of 1,2, or 3. In some embodiments, each subscript q is independently aninteger of 1 or 2. In some embodiments, each subscript q isindependently an integer of 1. In some embodiments, each subscript q isindependently an integer of 2.

In some embodiments, the subscript s is an integer of 1, 2, or 3. Insome embodiments, the subscript s is an integer of 1 or 2. In someembodiments, the subscript s is an integer of 1. In some embodiments,the subscript s is an integer of 2.

In some embodiments, provided herein is a compound of Formula (I) or(Ia), or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein:

ring A is 5- to 10-membered heteroaryl or 4- to 11-memberedheterocycloalkyl, wherein the 5- to 10-membered heteroaryl and 4- to11-membered heterocycloalkyl each has 1-4 heteroatoms as ring membersselected from N, O and S, wherein the N or S atom as ring members isoptionally oxidized and one or more carbon atoms as ring members areeach optionally replaced by a carbonyl group; and wherein ring A isoptionally substituted with 1, 2, or 3 R⁶ substituents;

L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, O, or —NR¹³—;

one of R¹ and R² is —(CR⁸R⁹)_(p)—NR¹⁰R¹¹ and the other is H, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, or OH, whereinthe C₁₋₄ alkyl and C₁₋₄ alkoxy of R¹ or R² is optionally substitutedwith 1 or 2 substituents independently selected from C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, NH₂, —NHC₁₋₄ alkyl and —N(C₁₋₄alkyl)₂;

R³ is methyl or halo;

R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, or OH;

R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, or OH;

each R⁶ is independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, CN, OR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), NHR^(a), NR^(a)R^(a), andNR^(a)C(O)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylof R⁶ are each optionally substituted with 1 or 2 R^(b) substituents;

R⁷ is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, or OH;

R⁸ and R⁹ are each independently selected from H, halo, CN, OH, —COOH,C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl,and C₁₋₄ haloalkoxy;

R¹⁰ and R¹¹ are each independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, —C(O)R^(g), —C(O)OR^(g), and —C(O)NR^(g)R^(g), wherein theC₁₋₆ alkyl and C₁₋₆ haloalkyl of R¹⁰ or R¹¹ are each optionallysubstituted with 1, 2 or 3 independently selected R^(f) substituents;

or R¹⁰ and R¹¹ taken together with the nitrogen atom to which they areattached form 4-, 5-, 6- or 7-membered heterocycloalkyl, wherein the 4-,5-, 6- or 7-membered heterocycloalkyl is optionally substituted with 1or 2 R^(h) substituents;

R¹² is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, or OH;

each R¹³ is independently H, C₁₋₆ haloalkyl or C₁₋₆ alkyl optionallysubstituted with a substituent selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, or OH;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl of R^(a) are each optionally substituted with1 or 2 R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, NH₂, OR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), NHR^(e),NR^(e)R^(e), and NR^(e)C(O)R^(e);

each R^(e) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, OR^(c), C(O)R^(c),C(O)NR^(c)R^(c), C(O)OR^(c), NHR^(c), NR^(c)R^(c), and NR^(c)C(O)R^(c);wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(b) are each further optionally substituted with 1 or 2independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl of R^(c) are each optionally substituted with 1, 2, or3 R^(f) substituents;

each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(g), C(O)R^(g),C(O)NR^(g)R^(g), C(O)OR^(g), NHR^(g), NR^(g)R^(g), and NR^(g)C(O)R^(g);

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(h) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(i),C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i), NHR^(i), NR^(i)R^(i), andNR^(i)C(O)R^(i);

each R^(i) is independently selected from H, C₁₋₄ alkyl, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

the subscript m is an integer of 0, 1 or 2;

the subscript n is an integer of 0, 1, or 2; and

the subscript p is an integer of 1, 2, or 3.

In some embodiments, provided herein is a compound of Formula (I) or(Ia), or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein:

ring A is 5- to 10-membered heteroaryl or 4- to 11-memberedheterocycloalkyl, wherein the 5- to 10-membered heteroaryl and 4- to11-membered heterocycloalkyl each has 1-4 heteroatoms as ring membersselected from N, O and S, wherein the N or S atom as ring members isoptionally oxidized and one or more carbon atoms as ring members areeach optionally replaced by a carbonyl group; and wherein ring A isoptionally substituted with 1 or 2 R⁶ substituents;

L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, or —NR¹³—;

one of R¹ and R² is —(CR⁸R⁹)_(p)—NR¹⁰R¹¹ and the other is H, C₁₋₄ alkyl,or C₁₋₄ alkoxy, wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy of R¹ or R² isoptionally substituted with 1 or 2 substituents independently selectedfrom C₁₋₄ alkoxy, CN, halo, OH, and NH₂;

R³ is methyl or halo;

R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, halo, or OH;

R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, halo, or OH;

each R⁶ is independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, CN, and OR^(a), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl of R⁶ are each optionally substituted with 1or 2 R^(b) substituents;

R⁷ is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, halo, or OH;

R⁸ and R⁹ are each independently selected from H, halo, CN, OH, and C₁₋₄alkyl;

R¹⁰ and R¹¹ are each independently selected from H, C₁₋₆ alkyl, and C₁₋₆haloalkyl, wherein the C₁₋₆ alkyl and C₁₋₆ haloalkyl of R¹⁰ or R¹¹ areeach optionally substituted with 1, 2 or 3 independently selected R^(f)substituents;

or R¹⁰ and R¹¹ taken together with the nitrogen atom to which they areattached form 4-, 5-, 6- or 7-membered heterocycloalkyl, wherein the 4-,5-, 6- or 7-membered heterocycloalkyl is optionally substituted with 1or 2 R^(h) substituents;

R¹² is H or C₁₋₄ alkyl;

each R¹³ is independently H or C₁₋₆ alkyl;

each R^(a) is independently selected from H and C₁₋₆ alkyl optionallysubstituted with 1 or 2 R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, and C(O)OR^(e);

each R^(e) is independently selected from H and C₁₋₆ alkyl;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, OH, NH₂,NHR^(c), NR^(c)R^(c), and NR^(c)C(O)R^(c); wherein the C₁₋₄ alkyl, 5-10membered heteroaryl, and 4-10 membered heterocycloalkyl of R^(b) areeach further optionally substituted with 1 or 2 independently selectedR^(d) substituents;

each R^(c) is independently selected from H and C₁₋₆ alkyl optionallysubstituted with 1, 2, or 3 R^(f) substituents;

each R^(f) is independently selected from C₁₋₄ alkyl, halo, CN, OR^(g),C(O)R^(g), C(O)NR^(g)R^(g), and C(O)OR^(g);

each R^(g) is independently selected from H and C₁₋₆ alkyl;

each R^(h) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, halo, OR^(i), C(O)R^(i), C(O)NR^(i)R^(i), and C(O)OR^(i);

each R^(i) is independently selected from H and C₁₋₄ alkyl;

the subscript m is an integer of 0 or 1;

the subscript n is an integer of 0 or 1; and

the subscript p is an integer of 1 or 2.

In some embodiments, provided herein is a compound of Formula (I) or(Ia), or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein:

ring A is 5- to 10-membered heteroaryl or 4- to 11-memberedheterocycloalkyl, wherein the 5- to 10-membered heteroaryl and 4- to11-membered heterocycloalkyl each has 1-4 heteroatoms as ring membersselected from N, O and S, wherein the N or S atom as ring members isoptionally oxidized and one or more carbon atoms as ring members areeach optionally replaced by a carbonyl group; and wherein ring A isoptionally substituted with 1, 2, or 3 R⁶ substituents;

L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, O, or —NR¹³—;

one of R¹ and R² is —(CR⁸R⁹)_(p)—NR¹⁰R¹¹ and the other is H, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, or OH, whereinthe C₁₋₄ alkyl and C₁₋₄ alkoxy of R¹ or R² is optionally substitutedwith 1 or 2 substituents independently selected from C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, NH₂, —NHC₁₋₄ alkyl and —N(C₁₋₄alkyl)₂;

R³ is methyl or halo;

R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, or OH;

R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, or OH;

each R⁶ is independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, CN, OR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), NHR^(a),NR^(a)R^(a), and NR^(a)C(O)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₃₋₁₀ cycloalkyl of R⁶ are each optionally substitutedwith 1 or 2 R^(b) substituents;

R⁷ is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, or OH;

R⁸ and R⁹ are each independently selected from H, halo, CN, OH, —COOH,C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl,and C₁₋₄ haloalkoxy;

R¹⁰ and R¹¹ are each independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, —C(O)R^(g), —C(O)OR^(g), and —C(O)NR^(g)R^(g), wherein theC₁₋₆ alkyl and C₁₋₆ haloalkyl of R¹⁰ or R¹¹ are each optionallysubstituted with 1, 2 or 3 independently selected R^(f) substituents;

or R¹⁰ and R¹¹ taken together with the nitrogen atom to which they areattached form 4-, 5-, 6- or 7-membered heterocycloalkyl, wherein the 4-,5-, 6- or 7-membered heterocycloalkyl is optionally substituted with 1or 2 R^(h) substituents;

R¹² is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, or OH;

each R¹³ is independently H, C₁₋₆ haloalkyl or C₁₋₆ alkyl optionallysubstituted with a substituent selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, or OH;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₁₀ cycloalkyl, wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₁₀ cycloalkyl of R^(a)are each optionally substituted with 1 or 2 R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,C₁₋₆ haloalkyl, halo, CN, NH₂, OR^(e), C(O)R^(e), C(O)NR^(e)R^(e),C(O)OR^(e), NHR^(e), NR^(e)R^(e), and NR^(e)C(O)R^(e), wherein the C₁₋₆alkyl and C₃₋₁₀ cycloalkyl of R^(d) are each optionally substituted with1, 2, or 3 independently selected R^(f) substituents;

each R^(e) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,CN, OH, NH₂, OR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), NHR^(c),NR^(c)R^(c), and NR^(c)C(O)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl-and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are eachfurther optionally substituted with 1 or 2 independently selected R^(d)substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl of R^(c) are each optionally substituted with 1, 2, or3 R^(f) substituents;

each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(g), C(O)R^(g),C(O)NR^(g)R^(g), C(O)OR^(g), NHR^(g), NR^(g)R^(g), and NR^(g)C(O)R^(g);

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(h) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(i),C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i), NHR^(i), NR^(i)R^(i), andNR^(i)C(O)R^(i);

each R^(i) is independently selected from H, C₁₋₄ alkyl, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

the subscript m is an integer of 0, 1 or 2;

the subscript n is an integer of 0, 1, or 2; and

the subscript p is an integer of 1, 2, or 3.

In some embodiments, provided herein is a compound of Formula (I) or(Ia), or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein:

ring A is 5- to 10-membered heteroaryl or 4- to 11-memberedheterocycloalkyl, wherein the 5- to 10-membered heteroaryl and 4- to11-membered heterocycloalkyl each has 1-4 heteroatoms as ring membersselected from N, O and S, wherein the N or S atom as ring members isoptionally oxidized and one or more carbon atoms as ring members areeach optionally replaced by a carbonyl group; and wherein ring A isoptionally substituted with 1 or 2 R⁶ substituents;

L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, or —NR¹³—;

one of R¹ and R² is —(CR⁸R⁹)_(p)—NR¹⁰R¹¹ and the other is H, C₁₋₄ alkyl,or C₁₋₄ alkoxy, wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy of R¹ or R² isoptionally substituted with 1 or 2 substituents independently selectedfrom C₁₋₄ alkoxy, CN, halo, OH, and NH₂;

R³ is methyl or halo;

R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, halo, or OH;

R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, halo, or OH;

each R⁶ is independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, CN, OR^(a), NHR^(a), NR^(a)R^(a), and C₃₋₁₀cycloalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₃₋₁₀ cycloalkyl of R⁶ are each optionally substituted with 1 or 2 R^(b)substituents;

R⁷ is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, halo, or OH;

R⁸ and R⁹ are each independently selected from H, halo, CN, OH, and C₁₋₄alkyl;

R¹⁰ and R¹¹ are each independently selected from H, C₁₋₆ alkyl, and C₁₋₆haloalkyl, wherein the C₁₋₆ alkyl and C₁₋₆ haloalkyl of R¹⁰ or R¹¹ areeach optionally substituted with 1, 2 or 3 independently selected R^(f)substituents;

or R¹⁰ and R¹¹ taken together with the nitrogen atom to which they areattached form 4-, 5-, 6- or 7-membered heterocycloalkyl, wherein the 4-,5-, 6- or 7-membered heterocycloalkyl is optionally substituted with 1or 2 R^(h) substituents;

R¹² is H or C₁₋₄ alkyl;

each R¹³ is independently H or C₁₋₆ alkyl;

each R^(a) is independently selected from H, C₁₋₆ alkyl, and C₃₋₁₀cycloalkyl optionally substituted with 1 or 2 R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,C₁₋₆ haloalkyl, halo, CN, OR^(e) and C(O)OR^(e), wherein the C₁₋₆ alkyland C₃₋₁₀ cycloalkyl of R^(d) are each optionally substituted with 1, 2,or 3 independently selected R^(f) substituents;

each R^(e) is independently selected from H and C₁₋₆ alkyl;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, CN, OH, NH₂, NHR^(c), NR^(c)R^(c), andNR^(c)C(O)R^(c); wherein the C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl of R^(b) are each furtheroptionally substituted with 1 or 2 independently selected R^(d)substituents;

each R^(c) is independently selected from H and C₁₋₆ alkyl optionallysubstituted with 1, 2, or 3 R^(f) substituents;

each R^(f) is independently selected from C₁₋₄ alkyl, halo, CN, OR^(g),C(O)R^(g), C(O)NR^(g)R^(g), and C(O)OR^(g);

each R^(g) is independently selected from H and C₁₋₆ alkyl;

each R^(h) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, halo, OR^(i), C(O)R^(i), C(O)NR^(i)R^(i), and C(O)OR^(i);

each R^(i) is independently selected from H and C₁₋₄ alkyl;

the subscript m is an integer of 0 or 1;

the subscript n is an integer of 0 or 1; and

the subscript p is an integer of 1 or 2.

In some embodiments, provided herein is a compound of Formula (I) or(Ia), or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein:

ring A is 5- to 10-membered heteroaryl, 4- to 11-memberedheterocycloalkyl, or C₆₋₁₀ aryl, wherein the 5- to 10-memberedheteroaryl and 4- to 11-membered heterocycloalkyl each has 1-4heteroatoms as ring members selected from N, O and S, wherein the N or Satom as ring members is optionally oxidized and one or more carbon atomsas ring members are each optionally replaced by a carbonyl group; andwherein ring A is optionally substituted with 1, 2, or 3 R⁶substituents;

L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, —(CR¹⁴R¹⁵)_(q)—O—, —O(CR¹⁴R¹⁵)_(q)—or —NR¹³—;

one of R¹ and R² is —(CR⁸R⁹)_(p)—NR¹⁰R¹¹ and the other is H, C₁₋₄ alkyl,or C₁₋₄ alkoxy, wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy of R¹ or R² isoptionally substituted with 1 or 2 substituents independently selectedfrom C₁₋₄ alkoxy, CN, halo, OH, and NH₂;

R³ is methyl or halo;

R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, halo, or OH;

R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, halo, or OH;

each R⁶ is independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, CN, OR^(a), NHR^(a), NR^(a)R^(a), C₃₋₁₀cycloalkyl, 4-14 membered heterocycloalkyl, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OR^(a), and C(O)R^(a), wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-14 memberedheterocycloalkyl, and (4-14 membered heterocycloalkyl)-C₁₋₄ alkyl- of R⁶are each optionally substituted with 1 or 2 R^(b) substituents;

each R¹³ is independently H or C₁₋₆ alkyl;

R¹⁴ and R¹⁵ are each independently selected from H and C₁₋₄ alkyl;

R⁷ is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, halo, or OH;

R⁸ and R⁹ are each independently selected from H, halo, CN, OH, and C₁₋₄alkyl;

R¹⁰ and R¹¹ are each independently selected from H, C₁₋₆ alkyl, and C₁₋₆haloalkyl, wherein the C₁₋₆ alkyl and C₁₋₆ haloalkyl of R¹⁰ or R¹¹ areeach optionally substituted with 1, 2 or 3 independently selected R^(f)substituents;

or R¹⁰ and R¹¹ taken together with the nitrogen atom to which they areattached form 4-, 5-, 6- or 7-membered heterocycloalkyl, wherein the 4-,5-, 6- or 7-membered heterocycloalkyl is optionally substituted with 1or 2 R^(h) substituents;

R¹² is H or C₁₋₄ alkyl;

each R¹³ is independently H or C₁₋₆ alkyl;

each R^(a) is independently selected from H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, 4-14 membered heterocycloalkyl, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-14 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-14 memberedheterocycloalkyl, (5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionallysubstituted with 1 or 2 independently selected R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-14 membered heterocycloalkyl, C₁₋₆ haloalkyl, halo, CN, OR^(e),C(O)OR^(e), NHR^(e), and NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, and 4-14 membered heterocycloalkyl of R^(d) are eachoptionally substituted with 1, 2, or 3 independently selected R^(f)substituents;

each R^(e) is independently selected from H and C₁₋₆ alkyl;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, CN, OH, OR^(c), C(O)NR^(c)R^(c), C(O)OR^(c), NH₂,NHR^(c), NR^(c)R^(c), and NR^(c)C(O)R^(c); wherein the C₁₋₄ alkyl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkylof R^(b) are each further optionally substituted with 1 or 2independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, and C₃₋₁₀cycloalkyl, wherein C₁₋₆ alkyl and C₃₋₁₀ cycloalkyl are each optionallysubstituted with 1, 2, or 3 R^(f) substituents;

each R^(f) is independently selected from C₁₋₄ alkyl, halo, CN, OR^(g),C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), and NR^(g)C(O)R^(g);

each R^(g) is independently selected from H and C₁₋₆ alkyl;

each R^(h) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, halo, OR^(i), C(O)R^(i), C(O)NR^(i)R^(i), and C(O)OR^(i);

each R^(i) is independently selected from H and C₁₋₄ alkyl;

the subscript m is an integer of 0 or 1;

the subscript n is an integer of 0 or 1; and

the subscript p is an integer of 1 or 2.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment (while theembodiments are intended to be combined as if written in multiplydependent form). Conversely, various features of the invention whichare, for brevity, described in the context of a single embodiment, canalso be provided separately or in any suitable subcombination. Thus, itis contemplated as features described as embodiments of the compounds ofFormula (I) can be combined in any suitable combination.

At various places in the present specification, certain features of thecompounds are disclosed in groups or in ranges. It is specificallyintended that such a disclosure include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually disclose(without limitation) methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl and C₆alkyl.

The term “n-membered,” where n is an integer, typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

At various places in the present specification, variables definingdivalent linking groups may be described. It is specifically intendedthat each linking substituent include both the forward and backwardforms of the linking substituent. For example, —NR(CR′R″)_(n)— includesboth —NR(CR′R″)_(n)— and —(CR′R″)_(n)NR— and is intended to discloseeach of the forms individually. Where the structure requires a linkinggroup, the Markush variables listed for that group are understood to belinking groups. For example, if the structure requires a linking groupand the Markush group definition for that variable lists “alkyl” or“aryl” then it is understood that the “alkyl” or “aryl” represents alinking alkylene group or arylene group, respectively.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. It is to be understood that substitution at a given atomresults in a chemically stable molecule. The phrase “optionallysubstituted” means unsubstituted or substituted. The term “substituted”means that a hydrogen atom is removed and replaced by a substituent. Asingle divalent substituent, e.g., oxo, can replace two hydrogen atoms.

The term “C_(n-m)” indicates a range which includes the endpoints,wherein n and m are integers and indicate the number of carbons.Examples include C₁₋₄, C₁₋₆ and the like.

The term “alkyl” employed alone or in combination with other terms,refers to a saturated hydrocarbon group that may be straight-chained orbranched. The term “C_(n-m) alkyl”, refers to an alkyl group having n tom carbon atoms. An alkyl group formally corresponds to an alkane withone C—H bond replaced by the point of attachment of the alkyl group tothe remainder of the compound. In some embodiments, the alkyl groupcontains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moietiesinclude, but are not limited to, chemical groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higherhomologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl and the like.

The term “alkenyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more double carbon-carbon bonds. Analkenyl group formally corresponds to an alkene with one C—H bondreplaced by the point of attachment of the alkenyl group to theremainder of the compound. The term “C_(n-m) alkenyl” refers to analkenyl group having n to m carbons. In some embodiments, the alkenylmoiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenylgroups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl and the like.

The term “alkynyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more triple carbon-carbon bonds. Analkynyl group formally corresponds to an alkyne with one C—H bondreplaced by the point of attachment of the alkyl group to the remainderof the compound. The term “C_(n-m) alkynyl” refers to an alkynyl grouphaving n to m carbons. Example alkynyl groups include, but are notlimited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In someembodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3carbon atoms.

The term “alkylene”, employed alone or in combination with other terms,refers to a divalent alkyl linking group. An alkylene group formallycorresponds to an alkane with two C—H bond replaced by points ofattachment of the alkylene group to the remainder of the compound. Theterm “C_(n-m) alkylene” refers to an alkylene group having n to m carbonatoms. Examples of alkylene groups include, but are not limited to,ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl,butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl and the like.

The term “alkoxy”, employed alone or in combination with other terms,refers to a group of formula —O-alkyl, wherein the alkyl group is asdefined above. The term “C_(n-m) alkoxy” refers to an alkoxy group, thealkyl group of which has n to m carbons. Example alkoxy groups includemethoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

The term “amino” refers to a group of formula —NH₂.

The term “carbamyl” refers to a group of formula —C(O)NH₂.

The term “carbonyl”, employed alone or in combination with other terms,refers to a —C(═O)— group, which also may be written as C(O).

The term “cyano” or “nitrile” refers to a group of formula —C≡N, whichalso may be written as —CN.

The terms “halo” or “halogen”, used alone or in combination with otherterms, refers to fluoro, chloro, bromo and iodo. In some embodiments,“halo” refers to a halogen atom selected from F, Cl, or Br. In someembodiments, halo groups are F.

The term “haloalkyl” as used herein refers to an alkyl group in whichone or more of the hydrogen atoms has been replaced by a halogen atom.The term “C_(n-m) haloalkyl” refers to a C_(n-m) alkyl group having n tom carbon atoms and from at least one up to {2(n to m)+1} halogen atoms,which may either be the same or different. In some embodiments, thehalogen atoms are fluoro atoms. In some embodiments, the haloalkyl grouphas 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅ and the like. In some embodiments, thehaloalkyl group is a fluoroalkyl group.

The term “haloalkoxy”, employed alone or in combination with otherterms, refers to a group of formula —O-haloalkyl, wherein the haloalkylgroup is as defined above. The term “C_(n-m) haloalkoxy” refers to ahaloalkoxy group, the haloalkyl group of which has n to m carbons.Example haloalkoxy groups include trifluoromethoxy and the like. In someembodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

The term “oxo” refers to an oxygen atom as a divalent substituent,forming a carbonyl group when attached to carbon, or attached to aheteroatom forming a sulfoxide or sulfone group, or an N-oxide group. Insome embodiments, heterocyclic groups may be optionally substituted by 1or 2 oxo (═O) substituents.

The term “sulfido” refers to a sulfur atom as a divalent substituent,forming a thiocarbonyl group (C═S) when attached to carbon.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized π (pi) electrons where n is an integer).

The term “aryl,” employed alone or in combination with other terms,refers to an aromatic hydrocarbon group, which may be monocyclic orpolycyclic (e.g., having 2 fused rings). The term “C_(n-m) aryl” refersto an aryl group having from n to m ring carbon atoms. Aryl groupsinclude, e.g., phenyl, naphthyl, indanyl, indenyl and the like. In someembodiments, aryl groups have from 6 to about 10 carbon atoms. In someembodiments aryl groups have 6 carbon atoms. In some embodiments arylgroups have 10 carbon atoms. In some embodiments, the aryl group isphenyl. In some embodiments, the aryl group is naphthyl.

The term “heteroatom” used herein is meant to include boron, phosphorus,sulfur, oxygen and nitrogen.

The term “heteroaryl” or “heteroaromatic,” employed alone or incombination with other terms, refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom boron, phosphorus, sulfur, oxygen and nitrogen. In someembodiments, the heteroaryl ring has 1, 2, 3 or 4 heteroatom ringmembers independently selected from nitrogen, sulfur and oxygen. In someembodiments, any ring-forming N in a heteroaryl moiety can be anN-oxide. In some embodiments, the heteroaryl has 5-14 ring atomsincluding carbon atoms and 1, 2, 3 or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl has 5-14, or 5-10 ring atoms includingcarbon atoms and 1, 2, 3 or 4 heteroatom ring members independentlyselected from nitrogen, sulfur and oxygen. In some embodiments, theheteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring. In other embodiments, the heteroaryl is aneight-membered, nine-membered or ten-membered fused bicyclic heteroarylring. Example heteroaryl groups include, but are not limited to,pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,pyrazolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl,quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-, 1,3-, 1,4-,1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridine), indolyl,benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl,purinyl, and the like.

A five-membered heteroaryl ring is a heteroaryl group having five ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary five-membered ring heteroarylsinclude thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

The term “cycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic hydrocarbon ring system (monocyclic,bicyclic or polycyclic), including cyclized alkyl and alkenyl groups.The term “C_(n-m) cycloalkyl” refers to a cycloalkyl that has n to mring member carbon atoms. Cycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles.Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14ring-forming carbons (C₃₋₁₄). In some embodiments, the cycloalkyl grouphas 3 to 14 members, 3 to 10 members, 3 to 6 ring members, 3 to 5 ringmembers, or 3 to 4 ring members. In some embodiments, the cycloalkylgroup is monocyclic. In some embodiments, the cycloalkyl group ismonocyclic or bicyclic. In some embodiments, the cycloalkyl group is aC₃₋₆ monocyclic cycloalkyl group. Ring-forming carbon atoms of acycloalkyl group can be optionally oxidized to form an oxo or sulfidogroup. Cycloalkyl groups also include cycloalkylidenes. In someembodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, e.g., benzo or thienyl derivativesof cyclopentane, cyclohexane and the like. A cycloalkyl group containinga fused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcaranyl,bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In someembodiments, the cycloalkyl group is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

The term “heterocycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic ring or ring system, which mayoptionally contain one or more alkenylene groups as part of the ringstructure, which has at least one heteroatom ring member independentlyselected from boron, nitrogen, sulfur oxygen and phosphorus, and whichhas 4-14 ring members, 4-10 ring members, 4-7 ring members, or 4-6 ringmembers. Included within the term “heterocycloalkyl” are monocyclic 4-,5-, 6- and 7-membered heterocycloalkyl groups. Heterocycloalkyl groupscan include mono- or bicyclic or polycyclic (e.g., having two or threefused or bridged rings) ring systems or spirorcycles. In someembodiments, the heterocycloalkyl group is a monocyclic group having 1,2 or 3 heteroatoms independently selected from nitrogen, sulfur andoxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkylgroup can be optionally oxidized to form an oxo or sulfido group orother oxidized linkage (e.g., C(O), S(O), C(S) or S(O)₂, N-oxide etc.)or a nitrogen atom can be quaternized. The heterocycloalkyl group can beattached through a ring-forming carbon atom or a ring-formingheteroatom. In some embodiments, the heterocycloalkyl group contains 0to 3 double bonds. In some embodiments, the heterocycloalkyl groupcontains 0 to 2 double bonds. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the heterocycloalkyl ring, e.g.,benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring. Examples of heterocycloalkyl groups include azetidinyl,azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl,morpholino, 3-oxa-9-azaspiro[5.5]undecanyl,1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl,pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl,tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl,4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, and thiomorpholino.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. One method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, e.g., optically active acids,such as the D and L forms of tartaric acid, diacetyltartaric acid,dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or thevarious optically active camphorsulfonic acids such as β-camphorsulfonicacid. Other resolving agents suitable for fractional crystallizationmethods include stereoisomerically pure forms of α-methylbenzylamine(e.g., S and R forms, or diastereomerically pure forms),2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the invention have the(R)-configuration. In other embodiments, the compounds have the(S)-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (S),unless otherwise indicated.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system,e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium. One ormore constituent atoms of the compounds of the invention can be replacedor substituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, the compound includes at least onedeuterium atom. For example, one or more hydrogen atoms in a compound ofthe present disclosure can be replaced or substituted by deuterium. Insome embodiments, the compound includes two or more deuterium atoms. Insome embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12 deuterium atoms. Synthetic methods for including isotopes intoorganic compounds are known in the art.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers and isotopes of thestructures depicted. The term is also meant to refer to compounds of theinventions, regardless of how they are prepared, e.g., synthetically,through biological process (e.g., metabolism or enzyme conversion), or acombination thereof.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated. When in the solid state, thecompounds described herein and salts thereof may occur in various formsand may, e.g., take the form of solvates, including hydrates. Thecompounds may be in any solid state form, such as a polymorph orsolvate, so unless clearly indicated otherwise, reference in thespecification to compounds and salts thereof should be understood asencompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, e.g., a composition enriched in the compounds of the invention.Substantial separation can include compositions containing at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, at least about 97%, or at leastabout 99% by weight of the compounds of the invention, or salt thereof.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, e.g., a temperature from about 20°C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. The term “pharmaceutically acceptablesalts” refers to derivatives of the disclosed compounds wherein theparent compound is modified by converting an existing acid or basemoiety to its salt form. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids; and the like. The pharmaceutically acceptable saltsof the present invention include the non-toxic salts of the parentcompound formed, e.g., from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J.Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook ofPharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). Insome embodiments, the compounds described herein include the N-oxideforms.

II. Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as those inthe Schemes below.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediatesor products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groupsin Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry or by chromatographic methods such as high performanceliquid chromatography (HPLC) or thin layer chromatography (TLC).

The Schemes below provide general guidance in connection with preparingthe compounds of the invention. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the invention.

Compounds of formula (I) can be prepared, e.g., using a process asillustrated in Schemes 1-4.

The compounds of Formula 1-3 can be prepared according to Scheme 1. Arylbromides 1-1 can react with boronates 1-2 under standard Suzuki couplingcondition (e.g., in the presence of a palladium catalyst and a suitablebase) to give the benzo[d]oxazol-2-yl substituted biaryl compounds 1-3.

The benzo[d]oxazol-2-yl substituted biaryl compounds of Formula 2-3 canbe prepared according to Scheme 2, starting from compounds of formula2-1 or 2-2 which can be prepared according to procedures as described inScheme 1. Briefly, the benzylic alcohols 2-1 can be transformed to thecorresponding aldehydes 2-3 by oxidation (e.g., Dess-Martin periodinaneas oxidant). The vinyl group in compounds 2-2 can be oxidatively cleavedby NaIO₄ in the presence of catalytic amount of OsO₄ or its equivalentsto form aldehydes 2-3. Then the aldehydes 2-3 react with amines offormula HNR¹⁰R¹¹ under standard reductive amination conditions (e.g.,sodium triacetoxyborohydride or sodium cyanoborohydride as reducingreagents) to generate compounds of formula 2-4.

The benzo[d]oxazol-2-yl substituted biaryl compounds of Formula 3-2 canbe prepared according to Scheme 3, starting from aldehydes of formula3-1. Briefly, Aldehydes 3-1 react with amines of formula HNR^(c)R^(c)under standard reductive amination conditions (e.g., sodiumtriacetoxyborohydride or sodium cyanoborohydride as reducing reagents)to generate compounds of formula 3-2.

The benzo[d]oxazol-2-yl substituted aryl boronates of Formula 4-6 can beprepared according to Scheme 4, starting from phenols of formula 4-1.Briefly, Phenols 4-1 can be nitrated to nitro compounds 4-2 understandard nitration condition (e.g., nitric acid as nitrating reagent inthe presence of acetic acid). The nitro compounds are reduced toanilines 4-3 either through Pd/C catalyzed hydrogenation or by ironpowder in acetic acid. The anilines 4-3 condense with aldehydes 4-4 inabsolute ethanol to afford dihydrobenzo[d]oxazole intermediates, whichcan be oxidized by dichlorodicyanoquinone to form benzo[d]oxazoles 4-5.The bromo group of benzo[d]oxazoles 4-5 can be converted to the boronicesters 4-6 under standard conditions [e.g., in the presence ofbis(pinacolato)diboron and a palladium catalyst, such as,tetrakis(triphenylphosphine) palladium(0), palladium(II) acetate].

III. Uses of the Compounds

Compounds of the present disclosure can inhibit the activity ofPD-1/PD-L1 protein/protein interaction and, thus, are useful in treatingdiseases and disorders associated with activity of PD-1 and the diseasesand disorders associated with PD-L1 including its interaction with otherproteins such as PD-1 and B7-1 (CD80). In certain embodiments, thecompounds of the present disclosure, or pharmaceutically acceptablesalts or stereoisomers thereof, are useful for therapeuticadministration to enhance, stimulate and/or increase immunity in cancer,chronic infection or sepsis, including enhancement of response tovaccination. In some embodiments, the present disclosure provides amethod for inhibiting the PD-1/PD-L1 protein/protein interaction. Themethod includes administering to an individual or a patient a compoundof Formula (I) or of any of the formulas as described herein, or of acompound as recited in any of the claims and described herein, or apharmaceutically acceptable salt or a stereoisomer thereof. Thecompounds of the present disclosure can be used alone, in combinationwith other agents or therapies or as an adjuvant or neoadjuvant for thetreatment of diseases or disorders, including cancer or infectiondiseases. For the uses described herein, any of the compounds of thedisclosure, including any of the embodiments thereof, may be used.

The compounds of the present disclosure inhibit the PD-1/PD-L1protein/protein interaction, resulting in a PD-1 pathway blockade. Theblockade of PD-1 can enhance the immune response to cancerous cells andinfectious diseases in mammals, including humans. In some embodiments,the present disclosure provides treatment of an individual or a patientin vivo using a compound of Formula (I) or a salt or stereoisomerthereof such that growth of cancerous tumors is inhibited. A compound ofFormula (I) or of any of the formulas as described herein, or a compoundas recited in any of the claims and described herein, or a salt orstereoisomer thereof, can be used to inhibit the growth of canceroustumors. Alternatively, a compound of Formula (I) or of any of theformulas as described herein, or a compound as recited in any of theclaims and described herein, or a salt or stereoisomer thereof, can beused in conjunction with other agents or standard cancer treatments, asdescribed below. In one embodiment, the present disclosure provides amethod for inhibiting growth of tumor cells in vitro. The methodincludes contacting the tumor cells in vitro with a compound of Formula(I) or of any of the formulas as described herein, or of a compound asrecited in any of the claims and described herein, or of a salt orstereoisomer thereof. In another embodiment, the present disclosureprovides a method for inhibiting growth of tumor cells in an individualor a patient. The method includes administering to the individual orpatient in need thereof a therapeutically effective amount of a compoundof Formula (I) or of any of the formulas as described herein, or of acompound as recited in any of the claims and described herein, or a saltor a stereoisomer thereof.

In some embodiments, provided herein is a method for treating cancer.The method includes administering to a patient in need thereof, atherapeutically effective amount of a compound of Formula (I) or any ofthe formulas as described herein, a compound as recited in any of theclaims and described herein, or a salt thereof. Examples of cancersinclude those whose growth may be inhibited using compounds of thedisclosure and cancers typically responsive to immunotherapy.

In some embodiments, the present disclosure provides a method ofenhancing, stimulating and/or increasing the immune response in apatient. The method includes administering to the patient in needthereof a therapeutically effective amount of a compound of Formula (I)or any of the formulas as described herein, a compound or composition asrecited in any of the claims and described herein, or a salt thereof.

Examples of cancers that are treatable using the compounds of thepresent disclosure include, but are not limited to, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectalcancer, cancer of the anal region, stomach cancer, testicular cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, endometrial cancer, carcinoma of the cervix, carcinoma ofthe vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin'slymphoma, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, chronic or acute leukemiasincluding acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors ofchildhood, lymphocytic lymphoma, cancer of the bladder, cancer of thekidney or urethra, carcinoma of the renal pelvis, neoplasm of thecentral nervous system (CNS), primary CNS lymphoma, tumor angiogenesis,spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi'ssarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos, andcombinations of said cancers. The compounds of the present disclosureare also useful for the treatment of metastatic cancers, especiallymetastatic cancers that express PD-Ll.

In some embodiments, cancers treatable with compounds of the presentdisclosure include melanoma (e.g., metastatic malignant melanoma), renalcancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormonerefractory prostate adenocarcinoma), breast cancer, colon cancer, lungcancer (e.g. non-small cell lung cancer and small cell lung cancer),squamous cell head and neck cancer, urothelial cancer (e.g. bladder) andcancers with high microsatellite instability (MSI^(high)). Additionally,the disclosure includes refractory or recurrent malignancies whosegrowth may be inhibited using the compounds of the disclosure.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to, solid tumors(e.g., prostate cancer, colon cancer, esophageal cancer, endometrialcancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer,pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancersof the head and neck, thyroid cancer, glioblastoma, sarcoma, bladdercancer, etc.), hematological cancers (e.g., lymphoma, leukemia such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed orrefractory NHL and recurrent follicular), Hodgkin lymphoma or multiplemyeloma) and combinations of said cancers.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to,cholangiocarcinoma, bile duct cancer, triple negative breast cancer,rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellularcarcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma,neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma,epithelioid sarcoma, eye cancer, Fallopian tube cancer, gastrointestinalcancer, gastrointestinal stromal tumors, hairy cell leukemia, intestinalcancer, islet cell cancer, oral cancer, mouth cancer, throat cancer,laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavitycancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer,renal cell carcinoma, salivary gland cancer, sinus cancer, spinalcancer, tongue cancer, tubular carcinoma, urethral cancer, and ureteralcancer.

In some embodiments, the compounds of the present disclosure can be usedto treat sickle cell disease and sickle cell anemia.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited tohematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), and essential thrombocytosis (ET)),myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma(T-ALL) and multiple myeloma (MM).

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, andteratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer, bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, and mesothelioma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma),large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma).

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors Exemplary nervous system cancers include cancers of the skull(osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma,glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors), and spinal cord (neurofibroma, meningioma, glioma,sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

Exemplary gynecological cancers include cancers of the uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma,angioma, dermatofibroma, and keloids. In some embodiments, diseases andindications that are treatable using the compounds of the presentdisclosure include, but are not limited to, sickle cell disease (e.g.,sickle cell anemia), triple-negative breast cancer (TNBC),myelodysplastic syndromes, testicular cancer, bile duct cancer,esophageal cancer, and urothelial carcinoma.

PD-1 pathway blockade with compounds of the present disclosure can alsobe used for treating infections such as viral, bacteria, fungus andparasite infections. The present disclosure provides a method fortreating infections such as viral infections. The method includesadministering to a patient in need thereof, a therapeutically effectiveamount of a compound of Formula (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,a salt thereof. Examples of viruses causing infections treatable bymethods of the present disclosure include, but are not limit to, humanimmunodeficiency virus, human papillomavirus, influenza, hepatitis A, B,C or D viruses, adenovirus, poxvirus, herpes simplex viruses, humancytomegalovirus, severe acute respiratory syndrome virus, ebola virus,and measles virus. In some embodiments, viruses causing infectionstreatable by methods of the present disclosure include, but are notlimit to, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6,HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus,flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus,respiratory syncytial virus, mumpsvirus, rotavirus, measles virus,rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus,papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus andarboviral encephalitis virus.

The present disclosure provides a method for treating bacterialinfections. The method includes administering to a patient in needthereof, a therapeutically effective amount of a compound of Formula (I)or any of the formulas as described herein, a compound as recited in anyof the claims and described herein, or a salt thereof. Non-limitingexamples of pathogenic bacteria causing infections treatable by methodsof the disclosure include Chlamydia, rickettsial bacteria, mycobacteria,staphylococci, streptococci, pneumonococci, meningococci and conococci,Klebsiella, Proteus, Serratia, Pseudomonas, Legionella, diphtheria,Salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague,leptospirosis, and Lyme's disease bacteria.

The present disclosure provides a method for treating fungus infections.The method includes administering to a patient in need thereof, atherapeutically effective amount of a compound of Formula (I) or any ofthe formulas as described herein, a compound as recited in any of theclaims and described herein, or a salt thereof. Non-limiting examples ofpathogenic fungi causing infections treatable by methods of thedisclosure include Candida (albicans, krusei, glabrata, tropicalis,etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.),Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii,Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioidesimmitis and Histoplasma capsulatum.

The present disclosure provides a method for treating parasiteinfections. The method includes administering to a patient in needthereof, a therapeutically effective amount of a compound of Formula (I)or any of the formulas as described herein, a compound as recited in anyof the claims and described herein, or a salt thereof. Non-limitingexamples of pathogenic parasites causing infections treatable by methodsof the disclosure include Entamoeba histolytica, Balantidium coli,Naegleria fowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidiumsp., Pneumocystis carinii, Plasmodium vivax, Babesia microti,Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasmagondi, and Nippostrongylus brasiliensis.

It is believed that compounds of Formula (I), or any of the embodimentsthereof, may possess satisfactory pharmacological profile and promisingbiopharmaceutical properties, such as toxicological profile, metabolismand pharmacokinetic properties, solubility, and permeability. It will beunderstood that determination of appropriate biopharmaceuticalproperties is within the knowledge of a person skilled in the art, e.g.,determination of cytotoxicity in cells or inhibition of certain targetsor channels to determine potential toxicity.

The terms “individual” or “patient,” used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Targeting more than one signaling pathway (or more than onebiological molecule involved in a given signaling pathway) may reducethe likelihood of drug-resistance arising in a cell population, and/orreduce the toxicity of treatment.

The compounds of the present disclosure can be used in combination withone or more other enzyme/protein/receptor inhibitors or one or moretherapies for the treatment of diseases, such as cancer or infections.Examples of diseases and indications treatable with combinationtherapies include those as described herein. Examples of cancers includesolid tumors and liquid tumors, such as blood cancers. Examples ofinfections include viral infections, bacterial infections, fungusinfections or parasite infections. For example, the compounds of thepresent disclosure can be combined with one or more inhibitors of thefollowing kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR,PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR,EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, PI3K(alpha, beta, gamma, delta), CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4,flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC,TAM kinases (Axl, Mer, Tyro3), FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2,EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK,ABL, ALK and B-Raf. In some embodiments, the compounds of the presentdisclosure can be combined with one or more of the following inhibitorsfor the treatment of cancer or infections. Non-limiting examples ofinhibitors that can be combined with the compounds of the presentdisclosure for treatment of cancer and infections include an FGFRinhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., INCB54828, INCB62079 andINCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g., ruxolitinib,baricitinib or INCB39110), an IDO inhibitor (e.g., epacadostat, NLG919,or BMS-986205), an LSD1 inhibitor (e.g., INCB59872 and INCB60003), a TDOinhibitor, a PI3K-delta inhibitor (e.g., INCB50797 and INCB50465), aPI3K-gamma inhibitor such as PI3K-gamma selective inhibitor, a Piminhibitor (e.g., INCB53914), a CSF1R inhibitor, a TAM receptor tyrosinekinases (Tyro-3, Axl, and Mer), an adenosine receptor antagonist (e.g.,A2a/A2b receptor antagonist), an HPK1 inhibitor, a histone deacetylaseinhibitor (HDAC) such as an HDAC8 inhibitor, an angiogenesis inhibitor,an interleukin receptor inhibitor, bromo and extra terminal familymembers inhibitors (for example, bromodomain inhibitors or BETinhibitors such as INCB54329 and INCB57643), a poly ADP ribosepolymerase (PARP) inhibitor such as rucaparib, olaparib, niraparib,veliparib, or talazoparib, an arginase inhibitor (INCB01158), and anadenosine receptor antagonist or combinations thereof.

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumor-targeted therapy, adjuvanttherapy, immunotherapy or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, adoptive T celltransfer, Toll receptor agonists, STING agonists, oncolytic virotherapyand immunomodulating small molecules, including thalidomide or JAK1/2inhibitor and the like. The compounds can be administered in combinationwith one or more anti-cancer drugs, such as a chemotherapeutics. Examplechemotherapeutics include any of: abarelix, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide,asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib,bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral,calusterone, capecitabine, carboplatin, carmustine, cetuximab,chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib,daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane,docetaxel, doxorubicin, dromostanolone propionate, eculizumab,epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide,exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine,fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumabozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan,idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lomustine, meclorethamine, megestrolacetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycinC, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine,nofetumomab, olaparib, oxaliplatin, paclitaxel, pamidronate,panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium,pentostatin, pipobroman, plicamycin, procarbazine, quinacrine,rasburicase, rituximab, ruxolitinib, rucaparib, sorafenib, streptozocin,sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide,testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene,tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin,vinblastine, vincristine, vinorelbine, vorinostat, niraparib, veliparib,talazoparib and zoledronate.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4 (e.g., ipilimumab), 4-1BB (e.g. urelumab, utomilumab), antibodiesto PD-1 and PD-L1, or antibodies to cytokines (IL-10, TGF-β, etc.).Examples of antibodies to PD-1 and/or PD-L1 that can be combined withcompounds of the present disclosure for the treatment of cancer orinfections such as viral, bacteria, fungus and parasite infectionsinclude, but are not limited to, nivolumab, pembrolizumab, MPDL3280A,MEDI-4736 and SHR-1210.

Compounds of the present disclosure can be used in combination with oneor more immune checkpoint inhibitors for the treatment of diseases, suchas cancer or infections. Exemplary immune checkpoint inhibitors includeinhibitors against immune checkpoint molecules such as CD27, CD28, CD40,CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma,TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4,BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1 and PD-L2. In someembodiments, the immune checkpoint molecule is a stimulatory checkpointmolecule selected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137. Insome embodiments, the immune checkpoint molecule is an inhibitorycheckpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO,KIR, LAG3, PD-1, TIM3, and VISTA. In some embodiments, the compoundsprovided herein can be used in combination with one or more agentsselected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160inhibitors, 2B4 inhibitors and TGFR beta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, orAMP-224. In some embodiments, the anti-PD-1 monoclonal antibody isnivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibodyis pembrolizumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525 or INCAGN2385.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228,BMS-986156, GWN323, or MEDI1873.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusionprotein. In some embodiments, the anti-OX40 antibody is MEDI0562,MOXR-0916, PF-04518600, GSK3174998, or BMS-986178. In some embodiments,the OX40L fusion protein is MEDI6383.

The compounds of the present disclosure can further be used incombination with one or more anti-inflammatory agents, steroids,immunosuppressants or therapeutic antibodies.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp100, MAGE antigens,Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to expressthe cytokine GM-CSF.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with a vaccination protocol forthe treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I) or any of the formulasas described herein, a compound as recited in any of the claims anddescribed herein, or salts thereof can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with vaccines, to stimulate theimmune response to pathogens, toxins, and self antigens. Examples ofpathogens for which this therapeutic approach may be particularlyuseful, include pathogens for which there is currently no effectivevaccine, or pathogens for which conventional vaccines are less thancompletely effective. These include, but are not limited to, HIV,Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania,Staphylococcus aureus, Pseudomonas aeruginosa.

Viruses causing infections treatable by methods of the presentdisclosure include, but are not limit to human papillomavirus,influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpessimplex viruses, human cytomegalovirus, severe acute respiratorysyndrome virus, ebola virus, measles virus, herpes virus (e.g., VZV,HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses,echovirus, rhinovirus, coxsackie virus, cornovirus, respiratorysyncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus,parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus,molluscum virus, poliovirus, rabies virus, JC virus and arboviralencephalitis virus.

Pathogenic bacteria causing infections treatable by methods of thedisclosure include, but are not limited to, Chlamydia, rickettsialbacteria, mycobacteria, staphylococci, streptococci, pneumonococci,meningococci and conococci, Klebsiella, Proteus, Serratia, Pseudomonas,Legionella, diphtheria, Salmonella, bacilli, cholera, tetanus, botulism,anthrax, plague, leptospirosis, and Lyme's disease bacteria.

Pathogenic fungi causing infections treatable by methods of thedisclosure include, but are not limited to, Candida (albicans, krusei,glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus(fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus),Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioidesbrasiliensis, Coccidioides immitis and Histoplasma capsulatum.

Pathogenic parasites causing infections treatable by methods of thedisclosure include, but are not limited to, Entamoeba histolytica,Balantidium coli, Naegleria fowleri, Acanthamoeba sp., Giardia lambia,Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesiamicroti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani,Toxoplasma gondi, and Nippostrongylus brasiliensis.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, separately, sequentially, or incombination (e.g., for more than two agents).

IV. Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the presentdisclosure can be administered in the form of pharmaceuticalcompositions. Thus the present disclosure provides a compositioncomprising a compound of Formula (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,or a pharmaceutically acceptable salt thereof, or any of the embodimentsthereof, and at least one pharmaceutically acceptable carrier orexcipient. These compositions can be prepared in a manner well known inthe pharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is indicated and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be,e.g., by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the present disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers or excipients. In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, e.g., a capsule, sachet, paper, orother container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, e.g., up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™). Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. In some embodiments, eachdosage contains about 10 mg of the active ingredient. In someembodiments, each dosage contains about 50 mg of the active ingredient.In some embodiments, each dosage contains about 25 mg of the activeingredient. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound may be effective over a wide dosage range and isgenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, e.g., about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers or stabilizers will resultin the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

V. Labeled Compounds and Assay Methods

The compounds of the present disclosure can further be useful ininvestigations of biological processes in normal and abnormal tissues.Thus, another aspect of the present invention relates to labeledcompounds of the invention (radio-labeled, fluorescent-labeled, etc.)that would be useful not only in imaging techniques but also in assays,both in vitro and in vivo, for localizing and quantitating PD-1 or PD-L1protein in tissue samples, including human, and for identifying PD-L1ligands by inhibition binding of a labeled compound. Accordingly, thepresent invention includes PD-1/PD-L1 binding assays that contain suchlabeled compounds.

The present invention further includes isotopically-substitutedcompounds of the disclosure. An “isotopically-substituted” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having the same atomic number but a differentatomic mass or mass number, e.g., a different atomic mass or mass numberfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). It is to be understood that a “radio-labeled”compound is a compound that has incorporated at least one isotope thatis radioactive (e.g., radionuclide). Suitable radionuclides that may beincorporated in compounds of the present invention include but are notlimited to ³H (also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N,¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, 35S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵Iand ¹³¹I. The radionuclide that is incorporated in the instantradio-labeled compounds will depend on the specific application of thatradio-labeled compound. For example, for in vitro PD-L1 protein labelingand competition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵,¹³¹I, ³⁵S or will generally be most useful. For radio-imagingapplications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br willgenerally be most useful.

In some embodiments the radionuclide is selected from the groupconsisting of ³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. Synthetic methods forincorporating radio-isotopes into organic compounds are known in theart.

Specifically, a labeled compound of the invention can be used in ascreening assay to identify and/or evaluate compounds. For example, anewly synthesized or identified compound (i.e., test compound) which islabeled can be evaluated for its ability to bind a PD-L1 protein bymonitoring its concentration variation when contacting with the PD-L1protein, through tracking of the labeling. For example, a test compound(labeled) can be evaluated for its ability to reduce binding of anothercompound which is known to bind to a PD-L1 protein (i.e., standardcompound). Accordingly, the ability of a test compound to compete withthe standard compound for binding to the PD-L1 protein directlycorrelates to its binding affinity. Conversely, in some other screeningassays, the standard compound is labeled and test compounds areunlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

VI. Kits

The present disclosure also includes pharmaceutical kits useful, e.g.,in the treatment or prevention of diseases or disorders associated withthe activity of PD-L1 including its interaction with other proteins suchas PD-1 and B7-1 (CD80), such as cancer or infections, which include oneor more containers containing a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (I), or any ofthe embodiments thereof. Such kits can further include one or more ofvarious conventional pharmaceutical kit components, such as, e.g.,containers with one or more pharmaceutically acceptable carriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to inhibitthe activity of PD-1/PD-L1 protein/protein interaction according to atleast one assay described herein.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Open Access Preparative LCMS Purification of some of thecompounds prepared was performed on Waters mass directed fractionationsystems. The basic equipment setup, protocols and control software forthe operation of these systems have been described in detail inliterature. See, e.g., Blom, “Two-Pump At Column Dilution Configurationfor Preparative LC-MS”, K. Blom, J. Combi. Chem., 2002, 4, 295-301; Blomet al., “Optimizing Preparative LC-MS Configurations and Methods forParallel Synthesis Purification”, J. Combi. Chem., 2003, 5, 670-83; andBlom et al., “Preparative LC-MS Purification: Improved Compound SpecificMethod Optimization”, J. Combi. Chem., 2004, 6, 874-883.

Example 1(S)-1-((7-chloro-2-(2′-chloro-3′-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2-methyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicAcid

Step 1: methyl 3-chloro-4-hydroxy-1-nitrobenzoate

To a solution of methyl 3-chloro-4-hydroxybenzoate (Alfa Aesar,#A512389: 10.0 g, 53.6 mmol) in acetic acid (20.0 mL, 352 mmol) wasadded a mixture of acetic acid (20.0 mL, 352 mmol) and nitric acid (4.72mL, 112 mmol) dropwise at 0° C. Then the ice bath was removed and thethick mixture was stirred at room temperature for 2 hrs. Then an equalvolume of water was added to the reaction suspension at 0° C. Themixture was filtered and washed with cold water. A yellow solid wasobtained as desired product without further purification. LC-MScalculated for C₈H₇ClNO₅ (M+H)⁺: m/z=232.0; found 232.0.

Step 2: methyl 3-amino-5-chloro-4-hydroxybenzoate

Methyl 3-chloro-4-hydroxy-5-nitrobenzoate (2.08 g, 8.98 mmol) washydrogenated under ambient pressure of hydrogen using palladium oncarbon (10 wt %, 0.57 g, 0.539 mmol) in ethyl acetate (15 mL) for 1 h.The resulting suspension was filtered through a pad of Celite and washedwith EtOAc and the solvent was removed under reduced pressure to give acrude product, which was purified by column chromatography (eluting withMeOH/DCM 0%-10%). LC-MS calculated for C₈H₉ClNO₃ (M+H)⁺: m/z=202.0;found 202.0.

Step 3: methyl2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazole-5-carboxylate

A mixture of methyl 3-amino-5-chloro-4-hydroxybenzoate (1.04 g, 5.16mmol), 3-bromo-2-methylbenzaldehyde (AstaTech, #52940: 0.98 g, 4.92mmol) in EtOH (25 ml) was placed in a vial and stirred at roomtemperature for 1 h. The mixture was then concentrated. The residue wasredissolved in methylene chloride (25 mL) and dichlorodicyanoquinone(1.12 g, 4.92 mmol) was added. The mixture was stirred at roomtemperature for 30 min. The reaction was diluted with methylene chlorideand washed with an aqueous Na₂S₂O₃ solution and NaHCO₃ solution. Theorganic phase was dried over MgSO₄, filtered and the filtrate wasconcentrated. The crude residue was used directly without furtherpurification. LC-MS calculated for C₁₆H₁₂BrClNO₃ (M+H)⁺: m/z=380.0,382.0; found 379.9, 381.9.

Step 4: (2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazol-5-yl)methanol

To a solution of methyl2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazole-5-carboxylate (395.0mg, 1.04 mmol) in DCM (10.0 ml) was added diisobutylaluminum hydride inDCM (1.0 M, 2.08 ml, 2.08 mmol) dropwise at −78° C. The mixture wasslowly warmed up to 0° C. Then the mixture was quenched with EtOAc andDCM, followed by aqueous Rochell's salt solution. The mixture wasstirred vigorously at room temperature for 1 h. The organic phase wasseparated and dried over MgSO₄ before filtering through a short pad ofCelite to remove solids. The filtrate was concentrated and purified bycolumn chromatography (eluting with 0-5% MeOH/DCM) to give the desiredproduct. LC-MS calculated for C₁₅H₁₂BrClNO₂ (M+H)⁺: m/z=352.0, 354.0;found 352.0, 354.0.

Step 5:(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol

A mixture of(2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazol-5-yl)methanol (113mg, 0.322 mmol), bis(pinacolato)diboron (98 mg, 0.386 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (26.3 mg, 0.032 mmol) and anhydrous potassiumacetate (79 mg, 0.804 mmol) in 1,4-dioxane (3.5 mL) was purged withnitrogen and stirred at 110° C. for 2 h. The crude was diluted with DCM,and then filtered through Celite. The filtrate was concentrated. Theresidue was purified by flash chromatography (eluting withEtOAc/Hexanes, 0-40%). LC-MS calculated for C₂₁H₂₄BClNO₄ (M+H)⁺:m/z=400.2; found 400.2.

Step 6: N-(3-bromo-2-chlorophenyl)-5-(dimethoxymethyl)picolinamide

To a solution of 3-bromo-2-chloroaniline (345 mg, 1.67 mmol) and methyl5-(dimethoxymethyl)picolinate (388 mg, 1.84 mmol) in THF (10 ml) wasadded potassium tert-butoxide in THF (1.0 M, 3.34 ml, 3.34 mmol) at roomtemperature, the mixture was stirred at this temperature for 2 hrs.Water was then added to quench the reaction. The mixture was extractedwith DCM three times. The organic phases were combined, dried overMgSO₄, filtered and the filtrate was concentrated. The residue was useddirectly without further purification. LC-MS calculated forC₁₅H₁₅BrClN₂O₃ (M+H)⁺: m/z=385.0; found 385.0.

Step 7:N-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(dimethoxymethyl)picolinamide

A mixture of N-(3-bromo-2-chlorophenyl)-5-(dimethoxymethyl)picolinamide(156 mg, 0.404 mmol),(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol(125 mg, 0.312 mmol), bis(dicyclohexylphosphino)ferrocene] palladium(II)(23.6 mg, 0.031 mmol) and cesium fluoride (119 mg, 0.780 mmol) in amixed water (300 μL) and 1,4-dioxane (1500 μlL was purged with N₂ andthen stirred at 100° C. for 3 hrs. The reaction was cooled to roomtemperature and then diluted with EtOAc and water. The aqueous phase wasextracted with EtOAc. The organic phase was dried over MgSO₄, filteredand the filtrate was concentrated under reduced pressure. The crudematerial was purified by flash chromatography on a silica gel (elutingwith MeOH/DCM, 0-10%) to give the desired product. LC-MS calculated forC₃₀H₂₆Cl₂N₃O₅ (M+H)⁺: m/z=578.1; found 578.1.

Step 8:N-(2-chloro-3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(dimethoxymethyl)picolinamide

ToN-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(dimethoxymethyl)picolinamide(189 mg, 0.327 mmol) and sodium bicarbonate (220 mg, 2.61 mmol) in DCM(2 mL) was added Dess-Martin periodinane (0.115 ml, 0.327 mmol) in oneportion at rt and the resulting mixture was stirred at room temperaturefor 20 min. The reaction was quenched by NaHCO₃ and Na₂S₂O₃ solution,extracted with DCM. The organic phase was dried over MgSO₄, filtered andthe filtrate was concentrated. The residue was used directly withoutfurther purification. LC-MS calculated for C₃₀H₂₄Cl₂N₃O₅ (M+H)⁺:m/z=576.1; found 576.1.

Step 9:(S)-1-((7-chloro-2-(2′-chloro-3′-(5-(dimethoxymethyl)picolinamido)-2-methyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicAcid

A mixture ofN-(2-chloro-3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(dimethoxymethyl)picolinamide(65.1 mg, 0.113 mmol) and (S)-piperidine-2-carboxylic acid (58.3 mg,0.452 mmol) in DCM (1129 μL) was stirred at room temperature for 2 hrs.Then sodium triacetoxyborohydride (71.8 mg, 0.339 mmol) and acetic acid(19.40 μl, 0.339 mmol) was added. The mixture was further stirred atroom temperature for 1 h. The reaction was diluted with DCM and quenchedby NH₃—H₂O. The organic layer was dried over MgSO₄, and concentrated andpurified by column chromatography (eluting with DCM/MeOH, 0-15%). LC-MScalculated for C₃₆H₃₅Cl₂N₄O₆ (M+H)⁺: m/z=689.2; found 689.4.

Step 10:(S)-1-((7-chloro-2-(2′-chloro-3′-(5-formylpicolinamido)-2-methyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicAcid

To a solution of(S)-1-((7-chloro-2-(2′-chloro-3′-(5-(dimethoxymethyl)picolinamido)-2-methyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicacid (35 mg, 0.051 mmol) in DCM (400 μL) was added TFA (117 μL, 1.51mmol) at room temperature. Then the mixture was stirred at roomtemperature for 1 h. The mixture was concentrated under vacuum beforebeing redissolved with DCM, quenched by aqueous NaHCO₃ solution. Theorganic phase was dried over MgSO₄, filtered and the filtrate wasconcentrated. The crude product was used directly in the next step.LC-MS calculated for C₃₄H₂₉Cl₂N₄O₅ (M+H)⁺: m/z=643.2; found 643.4.

Step 11:(S)-1-((7-chloro-2-(2′-chloro-3′-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2-methyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicAcid

A mixture of(S)-1-((7-chloro-2-(2′-chloro-3′-(5-formylpicolinamido)-2-methyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicacid (31.1 mg, 0.048 mmol) and 2-aminoethan-1-ol (11.8 mg, 0.19 mmol) inDCM (0.5 mL) was stirred at room temperature for 2 h. Then sodiumtriacetoxyborohydride (30.7 mg, 0.14 mmol) and acetic acid (8 μL, 0.14mmol) was added. The mixture was further stirred at room temperature for1 h. The reaction was diluted with MeOH and then purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as TFA salt.LC-MS calculated for C₃₆H₃₆Cl₂N₅O₅ (M+H)⁺: m/z=688.2; found 688.1.

Example 2(S)-1-((7-chloro-2-(2′-chloro-3′-(5-(((S)-3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-2-methyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicAcid

This compound was prepared using similar procedures as described forExample 1 with (S)-pyrrolidin-3-ol replacing ethanolamine in Step 11.The reaction was diluted with MeOH and then purified by prep-HPLC(pH=10, acetonitrile/water+NH₄OH) to give the desired product. LC-MScalculated for C₃₈H₃₈Cl₂N₅O₅ (M+H)⁺: m/z=714.2; found 714.2.

Example 3(S)-1-((7-chloro-2-(3′-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicAcid

Step 1: 8-chloro-3-vinyl-1,7-naphthyridine

A mixture of 3-bromo-8-chloro-1,7-naphthyridine (389 mg, 1.60 mmol)(PharmaBlock, cat #PBLJ2743),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (295 mg, 1.92 mmol),sodium carbonate (423 mg, 3.99 mmol) andbis(dicyclohexylphosphino)ferrocene] palladium(II) (60.4 mg, 0.080 mmol)in t-butanol (3.2 mL) and water (3.2 mL) was degassed and sealed. It wasstirred at 110° C. for 2 h. The reaction mixture was cooled thenextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over MgSO₄, filtered and concentrated under reducedpressure. The crude residue was used directly in the next step withoutfurther purification. LC-MS calculated for C₁₀H₈ClN₂ (M+H)⁺: m/z=191.0;found 191.0.

Step 2: N-(3-bromo-2-methylphenyl)-3-vinyl-1, 7-naphthyridin-8-amine

A mixture of 3-bromo-2-methylaniline (139 mg, 0.74 mmol),8-chloro-3-vinyl-1,7-naphthyridine (142 mg, 0.74 mmol) and HCl indioxane (4.0 M, 186 μL, 0.74 mmol) in t-butanol (3.7 mL) was heated at130° C. for 2 h. The reaction was then cooled to room temperature anddiluted with DCM. The reaction was quenched by aqueous NaHCO₃ solution,extracted with DCM. The organic phase was dried over MgSO₄, filtered andthe filtrate was concentrated. The residue was used directly for nextstep. LC-MS calculated for C₁₇H₁₅BrN₃ (M+H)⁺: m/z=340.0, 342.0; found340.1, 342.1.

Step 3:(7-chloro-2-(2,2′-dimethyl-3′-((3-vinyl-1,7-naphthyridin-8-yl)amino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanol

A mixture of N-(3-bromo-2-methylphenyl)-3-vinyl-1,7-naphthyridin-8-amine(81 mg, 0.24 mmol),(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol(95 mg, 0.24 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(18.7 mg, 0.024 mmol) and potassium phosphate (126 mg, 0.60 mmol) in amixed water (400 μl) and 1,4-dioxane (2.0 mL) was purged with N₂ andthen stirred at 70° C. for 1 h. The reaction was cooled to roomtemperature. The reaction mixture was diluted with ethyl acetate andthen washed with H₂O. The organic layer was dried over MgSO₄, filteredand concentrated to give a crude residue, which was purified by flashchromatography (eluting with MeOH/DCM, 0-10%). LC-MS calculated forC₃₂H₂₆ClN₄O₂ (M+H)⁺: m/z=533.2; found 533.2.

Step 4:7-chloro-2-(2,2′-dimethyl-3′-((3-vinyl-1,7-naphthyridin-8-yl)amino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-5-carbaldehyde

This compound was prepared using similar procedures as described forExample 1 with(7-chloro-2-(2,2′-dimethyl-3′-((3-vinyl-1,7-naphthyridin-8-yl)amino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanolreplacingN-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(dimethoxymethyl)picolinamidein Step 8. LC-MS calculated for C₃₂H₂₄ClN₄O₂ (M+H)⁺: m/z=531.2; found531.2.

Step 5:(S)-1-((7-chloro-2-(2,2′-dimethyl-3′-((3-vinyl-1,7-naphthyridin-8-yl)amino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicAcid

This compound was prepared using similar procedures as described forExample 1 with7-chloro-2-(2,2′-dimethyl-3′-((3-vinyl-1,7-naphthyridin-8-yl)amino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-5-carbaldehydereplacingN-(2-chloro-3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(dimethoxymethyl)picolinamidein Step 9. LC-MS calculated for C₃₈H₃₅ClN₅O₃ (M+H)⁺: m/z=644.2; found644.2.

Step 6:(S)-1-((7-chloro-2-(3′-((3-formyl-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicAcid

A vial was charged with(S)-1-((7-chloro-2-(2,2′-dimethyl-3′-((3-vinyl-1,7-naphthyridin-8-yl)amino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicacid (11 mg, 0.017 mmol), a stir bar, 1,4-dioxane (128 μL) and water (42μL). To this suspension was added osmium tetroxide (4% w/w in water, 6.7μl, 0.85 μmol). The reaction was stirred for 5 min then sodium periodate(18.2 mg, 0.085 mmol) was added. After stirring at room temperature for1 h, the reaction was quenched with a saturated aqueous solution ofsodium thiosulfate. The mixture was then extracted with ethyl acetate,and the combined organic layers were separated, washed with brine, driedover Na₂SO₄, filtered, and concentrated in vacuo. The crude residue wasused directly. LC-MS calculated for C₃₇H₃₃ClN₅O₄ (M+H)⁺: m/z=646.2;found 646.2.

Step 7:(S)-1-((7-chloro-2-(3′-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicAcid

This compound was prepared using similar procedures as described forExample 1 with(S)-1-((7-chloro-2-(3′-((3-formyl-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicacid (product from Step 6) replacing(S)-1-((7-chloro-2-(2′-chloro-3′-(5-formylpicolinamido)-2-methyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicacid in Step 11. The mixture was dissolved in MeOH then purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₃₉H₄₀ClN₆O₄ (M+H)⁺: m/z=691.3; found691.3.

Example 4(S)-1-((7-chloro-2-(3′-((3-(((2-hydroxy-2-methylpropyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicAcid

This compound was prepared using similar procedures as described forExample 3 with 1-amino-2-methylpropan-2-ol replacing ethanolamine inStep 7. The reaction was diluted with MeOH and then purified byprep-HPLC (pH=10, acetonitrile/water+NH₄OH) to give the desired product.LC-MS calculated for C₄₁H₄₄ClN₆O₄ (M+H)⁺: m/z=719.3; found 719.2.

Example 5(S)-1-((7-chloro-2-(3′-((3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicAcid

This compound was prepared using similar procedures as described forExample 3 with (S)-pyrrolidin-3-ol replacing ethanolamine in Step 7. Thereaction was diluted with MeOH and then purified by prep-HPLC (pH=10,acetonitrile/water+NH₄OH) to give the desired product. LC-MS calculatedfor C₄₁H₄₂ClN₆O₄ (M+H)⁺: m/z=717.3; found 717.2.

Example 63-(((7-chloro-2-(3′-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)amino)propanoicAcid

Step 1: methyl3-(((7-chloro-2-(2,2′-dimethyl-3′-((3-vinyl-1,7-naphthyridin-8-yl)amino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)amino)propanoate

This compound was prepared using similar procedures as described forExample 1 with7-chloro-2-(2,2′-dimethyl-3′-((3-vinyl-1,7-naphthyridin-8-yl)amino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-5-carbaldehyde(product from Step 4 in Example 3) replacingN-(2-chloro-3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(dimethoxymethyl)picolinamideand methyl 3-aminopropanoate hydrochloride salt replacing(S)-piperidine-2-carboxylic acid in Step 9. LC-MS calculated forC₃₆H₃₃ClN₅O₃ (M+H)⁺: m/z=618.2; found 618.2.

Step 2: methyl3-(((7-chloro-2-(3′-((3-formyl-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)amino)propanoate

This compound was prepared using similar procedures as described forExample 3 with methyl3-(((7-chloro-2-(2,2′-dimethyl-3′-((3-vinyl-1,7-naphthyridin-8-yl)amino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)amino)propanoate(product from Step 1) replacing(S)-1-((7-chloro-2-(2,2′-dimethyl-3′-((3-vinyl-1,7-naphthyridin-8-yl)amino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicacid in Step 6. LC-MS calculated for C₃₅H₃₁ClN₅O₄ (M+H)⁺: m/z=620.2;found 620.2.

Step 3: methyl3-(((7-chloro-2-(3′-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)amino)propanoate

This compound was prepared using similar procedures as described forExample 3 with methyl3-(((7-chloro-2-(3′-((3-formyl-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)amino)propanoatereplacing(S)-1-((7-chloro-2-(3′-((3-formyl-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicacid in Step 7. The reaction was diluted with DCM and quenched byNH₃—H₂O. The organic layer was dried over MgSO₄, filtered and thefiltrate was concentrated. The residue was purified by columnchromatography (eluting with DCM/MeOH, 0-10%). LC-MS calculated forC₃₇H₃₈ClN₆O₄ (M+H)⁺: m/z=665.3; found 665.3.

Step 4:3-(((7-chloro-2-(3′-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)amino)propanoicAcid

To a solution of methyl3-(((7-chloro-2-(3′-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)amino)propanoate(10.0 mg, 0.015 mmol) in a mixture of water (63 μL), THF (125 μL) andMeOH (63 μL) was added lithium hydroxide (3.6 mg, 0.15 mmol). Thereaction was stirred at room temperature for 2 h. The reaction wasdiluted with MeOH and then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₃₆H₃₆ClN₆O₄ (M+H)⁺: m/z=651.2; found 651.2.

Example 7(2S,2′S)-1,1′-(((2,2′-dimethyl-[1,1′-biphenyl]-3,3′-diyl)bis(6-(cyanomethoxy)benzo[d]oxazole-2,5-diyl))bis(methylene))bis(piperidine-2-carboxylic Acid)

Step 1: methyl 2,4-dihydroxy-5-nitrobenzoate

To a solution of methyl 2,4-dihydroxybenzoate (Aldrich, cat #M42505:9.15 g, 54.4 mmol) in acetic anhydride (34 mL) and acetic acid (66 mL)was slowly added mixture of nitric acid (3.82 mL, 63.8 mmol) in aceticacid (30 mL) at 0° C. After addition, a light brown solution was formed.Then the mixture was stirred at room temperature for 30 min, after whicha suspension had formed. Water (130 mL) was added, whereupon the mixturewas aged for another 30 min without stirring. The precipitate wasfiltered, rinsed with small amount of water, and dried under vacuum togive crude product, which was used directly in the next step withoutfurther purification. LC-MS calculated for C₈H₈NO₆ (M+H)⁺: m/z=214.0;found 214.0.

Step 2: methyl 5-amino-2,4-dihydroxybenzoate

Methyl 2, 4-dihydroxy-5-nitrobenzoate (592 mg, 2.78 mmol) washydrogenated under ambient pressure of hydrogen using palladium oncarbon (10 wt %, 300 mg, 0.28 mmol) in ethyl acetate (30 mL) for 3 h.The resulting suspension was filtered through a pad of Celite, washedwith ethyl acetate and the solvent was removed under reduced pressure togive crude product, which was used directly without furtherpurification. LC-MS calculated for C₈H₁₀NO₄ (M+H)⁺: m/z=184.1; found184.0.

Step 3: methyl2-(3-bromo-2-methylphenyl)-6-hydroxybenzo[d]oxazole-5-carboxylate

This compound was prepared using similar procedures as described forExample 1 with methyl 5-amino-2,4-dihydroxybenzoate replacing methyl3-amino-5-chloro-4-hydroxybenzoate in Step 3. LC-MS calculated forC₁₆H₁₃BrNO₄ (M+H)⁺: m/z=362.0, 364.0; found 362.0, 364.0.

Step 4: 2-(3-bromo-2-methylphenyl)-5-(hydroxymethyl)benzo[d]oxazol-6-ol

This compound was prepared using similar procedures as described forExample 1 with methyl2-(3-bromo-2-methylphenyl)-6-hydroxy-2,3-dihydrobenzo[d]oxazole-5-carboxylatereplacing methyl2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazole-5-carboxylate in Step4. LC-MS calculated for C₁₅H₁₃BrNO₃ (M+H)⁺: m/z=334.0, 336.0; found334.0, 336.0.

Step 5:2-((2-(3-bromo-2-methylphenyl)-5-(hydroxymethyl)benzo[d]oxazol-6-yl)oxy)acetonitrile

To a solution of 2-bromoacetonitrile (219 mg, 1.82 mmol) and2-(3-bromo-2-methylphenyl)-5-(hydroxymethyl)benzo[d]oxazol-6-ol (406.6mg, 1.22 mmol) in DMF (2.5 mL) was added potassium carbonate (336 mg,2.43 mmol). The mixture was heated up to 60° C. for 1 h. The reactionwas then cooled to room temperature and diluted with EtOAc, quenchedwith water. After extraction, the organic phase was dried over MgSO₄,filtered and the filtrate was concentrated. The residue was useddirectly without further purification. LC-MS calculated for C₁₇H₁₄BrN₂O₃(M+H)⁺: m/z=373.0, 375.0; found 373.0, 375.0

Step 6:2-((5-(hydroxymethyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-6-yl)oxy)acetonitrile

This compound was prepared using similar procedures as described forExample 1 with2-((2-(3-bromo-2-methylphenyl)-5-(hydroxymethyl)benzo[d]oxazol-6-yl)oxy)acetonitrilereplacing(2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazol-5-yl)methanol in Step5. LC-MS calculated for C₂₃H₂₆BN₂O₅ (M+H)⁺: m/z=421.2; found 421.2.

Step 7:2,2′-(((2,2′-dimethyl-[1,1′-biphenyl]-3,3′-diyl)bis(5-(hydroxymethyl)benzo[d]oxazole-2,6-diyl))bis(oxy))diacetonitrile

This compound was prepared using similar procedures as described forExample 1 with2-((5-(hydroxymethyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-6-yl)oxy)acetonitrile(product from Step 6) replacing(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol,2-((2-(3-bromo-2-methylphenyl)-5-(hydroxymethyl)benzo[d]oxazol-6-yl)oxy)acetonitrile(product from Step 5) replacingN-(3-bromo-2-chlorophenyl)-5-(dimethoxymethyl)picolinamide and potassiumcarbonate replacing cesium fluoride in Step 7. LC-MS calculated forC₃₄H₂₇N₄O₆ (M+H)⁺: m/z=587.2; found 587.2.

Step 8:2,2′-(((2,2′-dimethyl-[1,1′-biphenyl]-3,3′-diyl)bis(5-formylbenzo[d]oxazole-2,6-diyl))bis(oxy))diacetonitrile

This compound was prepared using similar procedures as described forExample 1 with2,2′-(((2,2′-dimethyl-[1,1′-biphenyl]-3,3′-diyl)bis(5-(hydroxymethyl)benzo[d]oxazole-2,6-diyl))bis(oxy))diacetonitrilereplacing N-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(dimethoxymethyl)picolinamideand two equivalents of Dess-Martin periodinane in Step 8. LC-MScalculated for C₃₄H₂₃N₄O₆ (M+H)⁺: m/z=583.2; found 583.2.

Step 9:(2S,2′S)-1,1′-(((2,2′-dimethyl-[1,1′-biphenyl]-3,3′-diyl)bis(6-(cyanomethoxy)benzo[d]oxazole-2,5-diyl))bis(methylene))bis(piperidine-2-carboxylicAcid)

This compound was prepared using similar procedures as described forExample 1 with2,2′-(((2,2′-dimethyl-[1,1′-biphenyl]-3,3′-diyl)bis(5-formylbenzo[d]oxazole-2,6-diyl))bis(oxy))diacetonitrile(product from step 8) replacingN-(2-chloro-3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(dimethoxymethyl)picolinamidein Step 9. The reaction mixture was diluted with methanol and thenpurified by prep-HPLC (pH=10, acetonitrile/water+NH₄OH) to give thedesired product. LC-MS calculated for C₄₆H₄₅N₆O₈ (M+H)⁺: m/z=809.3;found 809.2.

Example 8(S)-1-((7-chloro-2-(2′-chloro-2-methyl-3′-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicAcid

Step 1:N-(3-bromo-2-chlorophenyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

To a solution of 3-bromo-2-chloroaniline (174 mg, 0.84 mmol) and5-(tert-butyl) 2-ethyl6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-dicarboxylate (528 mg, 1.69mmol) in THF (5.5 mL) was added potassium tert-butoxide in THF (1.0 M,1.27 mL, 1.27 mmol) at −10° C. The mixture was stirred and slowly warmedup to 0° C. for 1 h. Water was then added to quench the reaction. Themixture was extracted with DCM. The organic phase was dried over MgSO₄and concentrated. The residue was redissolved in DCM. The DCM solutionwas treated with TFA (0.19 mL, 2.52 mmol). The volatile was removedunder reduced pressure after 1 h. The residue was used for next stepdirectly. LC-MS calculated for C₁₃H₁₂BrClN₃OS (M+H)⁺: m/z=372.0; found371.9.

Step 2:N-(3-bromo-2-chlorophenyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

A mixture of N-(3-bromo-2-chlorophenyl)-4, 5, 6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide (61 mg, 0.16 mmol) andformaldehyde (37% in water, 66 mg, 0.82 mmol) in DCM (500 μL) wasstirred at rt for 2 h. Then sodium triacetoxyborohydride (104 mg, 0.49mmol) and acetic acid (28 μL, 0.49 mmol) was added. The mixture wasfurther stirred at room temperature for 1 h. The reaction was quenchedby NH₄OH, then extracted with DCM. The organic phase was dried overMgSO₄, filtered and the filtrate was concentrated. The residue waspurified by column chromotography (eluting with MeOH/DCM, 0-10%). LC-MScalculated for C₁₄H₁₄BrClN₃OS (M+H)⁺: m/z=386.0/388.0; found385.9/387.9.

Step 3:N-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

This compound was prepared using similar procedures as described forExample 1 withN-(3-bromo-2-chlorophenyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide(product from Step 2) replacingN-(3-bromo-2-chlorophenyl)-5-(dimethoxymethyl)picolinamide andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)replacing bis(dicyclohexylphosphino)ferrocene] palladium(II) in Step 7.LC-MS calculated for C₂₉H₂₅Cl₂N₄O₃S (M+H)⁺: m/z=579.1; found 579.1.

Step 4:N-(2-chloro-3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

This compound was prepared using similar procedures as described forExample 1 withN-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide(product from step 3) replacingN-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(dimethoxymethyl)picolinamidein Step 8. LC-MS calculated for C₂₉H₂₃Cl₂N₄O₃S (M+H)⁺: m/z=577.1; found577.1.

Step 5:(S)-1-((7-chloro-2-(2′-chloro-2-methyl-3′-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicAcid

This compound was prepared using similar procedures as described forExample 1 withN-(2-chloro-3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide(product from step 4) replacingN-(2-chloro-3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(dimethoxymethyl)picolinamidein Step 9. The reaction mixture was diluted with MeOH and then purifiedby prep-HPLC (pH=10, acetonitrile/water+NH₄OH) to give the desiredproduct. LC-MS calculated for C₃₅H₃₄Cl₂N₅O₄S (M+H)⁺: m/z=690.2; found690.2.

Example 9N-(2-chloro-3′-(7-chloro-5-(((2-hydroxyethyl)amino)methyl)benzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

This compound was prepared using similar procedures as described forExample 1 withN-(2-chloro-3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide(product from step 4) replacing(S)-1-((7-chloro-2-(2′-chloro-3′-(5-formylpicolinamido)-2-methyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicacid in Step 11. The reaction was diluted with MeOH and then purified byprep-HPLC (pH=10, acetonitrile/water+NH₄OH) to give the desired product.LC-MS calculated for C₃₁H₃₀Cl₂N₅O₃S (M+H)⁺: m/z=622.1; found 622.2.

Example 10(S)-1-((7-chloro-2-(3′-(7-chloro-5-(((S)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazole-5-carbaldehyde

This compound was prepared using similar procedures as described forExample 1, Step 8 with(2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazol-5-yl)methanol(Example 1, Step 4) replacingN-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(dimethoxymethyl)picolinamide.LC-MS calculated for C₁₅H₁₀BrClNO₂ (M+H)⁺: m/z=350.0; found 350.0.

Step 2:(S)-1-((2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazol-5-yl)methyl)pyrrolidin-3-ol

This compound was prepared using similar procedures as described forExample 1, Step 11 with (S)-pyrrolidin-3-ol replacing ethanolamine and2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazole-5-carbaldehydereplacing(S)-1-((7-chloro-2-(2′-chloro-3′-(5-formylpicolinamido)-2-methyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicacid. The reaction was quenched by NH₄OH aqueous solution and extractedwith DCM. The organic phase was combined and dried over MgSO₄, thenfiltered. The filtrate was concentrated and purified by columnchromatography (0-5% MeOH in DCM). LC-MS calculated for C₁₉H₁₉BrClN₂O₂(M+H)⁺: m/z=421.0; found 421.1.

Step 3:(S)-1-((7-chloro-2-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidin-3-ol

A mixture of(S)-1-((2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazol-5-yl)methyl)pyrrolidin-3-ol(38 mg, 0.09 mmol),(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol(Example 1, Step 5: 39 mg, 0.10 mmol), sodium carbonate (24 mg, 0.22mmol) and tetrakis(triphenylphosphine)palladium(0) (10 mg, 8.9 μmol) ina mixed water (150 μl) and 1,4-dioxane (750 μl) was purged with N₂ andthen stirred at 100° C. for 2 h. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate and then washed with H₂O. Theorganic layer was dried MgSO₄, filtered and concentrated to give a cruderesidue, which was purified by flash chromatography on a silica gelcolumn eluting with 0 to 10% MeOH/DCM to give the desired product. LC-MScalculated for C₃₄H₃₀Cl₂N₃O₄ (M+H)⁺: m/z=614.2; found 614.2.

Step 4:(S)-7-chloro-2-(3′-(7-chloro-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-carbaldehyde

A suspension of(S)-1-((7-chloro-2-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidin-3-ol(31 mg, 0.050 mmol) and manganese dioxide (110 mg, 1.26 mmol) in DCM(500 μl) was stirred at 45° C. for 15 min. The reaction was filteredthrough a short pad of celite and then concentrated to yield a cruderesidue, which was used directly without further purification. LC-MScalculated for C₃₄H₂₈Cl₂N₃O₄ (M+H)⁺: m/z=612.2; found 612.2.

Step 5:(S)-1-((7-chloro-2-(3′-(7-chloro-5-(((S)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 1, Step 9 with(S)-7-chloro-2-(3′-(7-chloro-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-carbaldehyde(product from Step 4) replacingN-(2-chloro-3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(dimethoxymethyl)picolinamideand (S)-pyrrolidine-3-carboxylic acid replacing(S)-piperidine-2-carboxylic acid. The reaction mixture was diluted withMeOH and then purified by prep-HPLC (pH=10, acetonitrile/water+NH₄OH) togive the desired product. LC-MS calculated for C₃₉H₃₇Cl₂N₄O₅ (M+H)⁺:m/z=711.2; found 711.2.

Example 11(R)-1-((7-chloro-2-(2,2′-dimethyl-3′-(pyrido[4,3-b]pyrazin-5-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: N-(3-bromo-2-methylphenyl)pyrido[4,3-b]pyrazin-5-amine

This compound was prepared using similar procedures as described forExample 3, Step 2 with 5-chloropyrido[4,3-b]pyrazine (Aurum Pharmatech,#C-1958) replacing 8-chloro-3-vinyl-1,7-naphthyridine. LC-MS calculatedfor C₁₄H₁₂BrN₄ (M+H)⁺: m/z=315.0; found 315.0.

Step 2:(7-chloro-2-(2,2′-dimethyl-3′-(pyrido[4,3-b]pyrazin-5-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methanol

This compound was prepared using similar procedures as described forExample 10, Step 3 withN-(3-bromo-2-methylphenyl)pyrido[4,3-b]pyrazin-5-amine replacing(S)-1-((2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazol-5-yl)methyl)pyrrolidin-3-ol.LC-MS calculated for C₂₉H₂₃ClN₅O₂ (M+H)⁺: m/z=508.2; found 508.2.

Step 3:7-chloro-2-(2,2′-dimethyl-3′-(pyrido[4,3-b]pyrazin-5-ylamino)biphenyl-3-yl)benzo[d]oxazole-5-carbaldehyde

This compound was prepared using similar procedures as described forExample 10, Step 4 with(7-chloro-2-(2,2′-dimethyl-3′-(pyrido[4,3-b]pyrazin-5-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methanolreplacing(S)-1-((7-chloro-2-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidin-3-ol.LC-MS calculated for C₂₉H₂₁ClN₅O₂ (M+H)⁺: m/z=506.1; found 506.2.

Step 4:(R)-1-((7-chloro-2-(2,2′-dimethyl-3′-(pyrido[4,3-b]pyrazin-5-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 1, Step 9 with7-chloro-2-(2,2′-dimethyl-3′-(pyrido[4,3-b]pyrazin-5-ylamino)biphenyl-3-yl)benzo[d]oxazole-5-carbaldehyde (product from Step 3) replacingN-(2-chloro-3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(dimethoxymethyl)picolinamideand (R)-pyrrolidine-3-carboxylic acid replacing(S)-piperidine-2-carboxylic acid. The reaction was diluted with MeOH andthen purified by prep-HPLC (pH=10, acetonitrile/water+NH₄OH) to give thedesired product. LC-MS calculated for C₃₄H₃₀ClN₆O₃ (M+H)⁺: m/z=605.2;found 605.2.

Example 12(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(pyrido[4,3-b]pyrazin-5-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:2-(2,2′-dimethyl-3′-(pyrido[4,3-b]pyrazin-5-ylamino)biphenyl-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrile

A mixture of(7-chloro-2-(2,2′-dimethyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanol(Example 11, product from Step 2, 14.7 mg, 0.029 mmol),[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (2.3 mg, 2.9 μmol), potassiumhexacyanoferrate(II) trihydrate (12.2 mg, 0.029 mmol) and potassiumacetate (5.7 mg, 0.058 mmol) in a mixed 1,4-dioxane (250 μl) and water(250 μl) was stirred and heated at 100° C. for 2 h. After cooling toroom temperature, the reaction mixture was diluted with EtOAc and water,extracted with EtOAc. The combined organic phase was dried over MgSO₄,and then filtered. The filtrate was concentrated. The crude material waspurified by column chromatography (0-8% MeOH in DCM) to give the desiredproduct. LC-MS calculated for C₃₀H₂₃N₆O₂ (M+H)⁺: m/z=499.2; found 499.2.

Step 2:2-(2,2′-dimethyl-3′-(pyrido[4,3-b]pyrazin-5-ylamino)biphenyl-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile

This compound was prepared using similar procedures as described forExample 10, Step 4 with2-(2,2′-dimethyl-3′-(pyrido[4,3-b]pyrazin-5-ylamino)biphenyl-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrile replacing(S)-1-((7-chloro-2-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidin-3-ol.LC-MS calculated for C₃₀H₂₁N₆O₂ (M+H)⁺: m/z=497.2; found 497.2.

Step 3:(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(pyrido[4,3-b]pyrazin-5-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 1, Step 9 with2-(2,2′-dimethyl-3′-(pyrido[4,3-b]pyrazin-5-ylamino)biphenyl-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile replacingN-(2-chloro-3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(dimethoxymethyl)picolinamideand (R)-pyrrolidine-3-carboxylic acid replacing(S)-piperidine-2-carboxylic acid. The reaction was diluted with MeOH andthen purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₃₅H₃₀N₇O₃ (M+H)⁺:m/z=596.2; found 596.2. ¹H NMR (600 MHz, 330K, CD₃CN, with T2 filter) δ9.07 (d, J=1.8 Hz, 1H), 8.84 (d, J=1.9 Hz, 1H), 8.23 (dd, J=7.5, 1.4 Hz,3H), 8.19 (d, J=6.3 Hz, 1H), 7.95 (d, J=1.5 Hz, 1H), 7.54 (t, J=7.8 Hz,1H), 7.46 (dd, J=7.5, 1.4 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.29 (d,J=6.2 Hz, 1H), 7.12-7.07 (m, 1H), 4.48 (d, J=1.6 Hz, 2H), 3.70-3.49 (m,2H), 3.49-3.28 (m, 3H), 2.53 (s, 3H), 2.47-2.24 (m, 2H), 2.12 (s, 3H).

Example 13(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(pyrido[3,2-d]pyrimidin-4-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: N-(3-bromo-2-methylphenyl)pyrido[3,2-d]pyrimidin-4-amine

This compound was prepared using similar procedures as described forExample 3, Step 2 with 4-chloropyrido[3,2-d]pyrimidine replacing8-chloro-3-vinyl-1,7-naphthyridine. LC-MS calculated for C₁₄H₁₂BrN₄(M+H)⁺: m/z=315.0; found 315.0.

Step 2:(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(pyrido[3,2-d]pyrimidin-4-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 12 with N-(3-bromo-2-methylphenyl)pyrido[3,2-d]pyrimidin-4-aminereplacing N-(3-bromo-2-methylphenyl)pyrido[4,3-b]pyrazin-5-amine. Thereaction was diluted with MeOH and then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₃₅H₃₀N₇O₃ (M+H)⁺: m/z=596.2; found 596.2.

Example 14(R)-1-((2-(2′-chloro-2-methyl-3′-(pyrido[4,3-b]pyrazin-5-ylamino)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: N-(3-bromo-2-chlorophenyl)pyrido[4,3-b]pyrazin-5-amine

This compound was prepared using similar procedures as described forExample 3, Step 2 with 3-bromo-2-chloroaniline replacing3-bromo-2-methylaniline and 5-chloropyrido[4,3-b]pyrazine replacing8-chloro-3-vinyl-1,7-naphthyridine. LC-MS calculated for C₁₃H₉BrClN₄(M+H)⁺: m/z=335.0; found 335.0.

Step 2:(R)-1-((2-(2′-chloro-2-methyl-3′-(pyrido[4,3-b]pyrazin-5-ylamino)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 12 with N-(3-bromo-2-chlorophenyl)pyrido[4,3-b]pyrazin-5-aminereplacing N-(3-bromo-2-methylphenyl)pyrido[4,3-b]pyrazin-5-amine. Thereaction was diluted with MeOH and then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₃₄H₂₇ClN₇O₃ (M+H)⁺: m/z=616.2; found 616.1.

Example 15(R)-1-((2-(2′-chloro-2-methyl-3′-(pyrido[3,4-b]pyrazin-8-ylamino)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:(2-(3′-amino-2′-chloro-2-methylbiphenyl-3-yl)-7-chlorobenzo[d]oxazol-5-yl)methanol

A mixture of 3-bromo-2-chloroaniline (222 mg, 1.08 mmol),(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol(535 mg, 0.977 mmol), sodium carbonate (259 mg, 2.44 mmol) andtetrakis(triphenylphosphine) palladium(0) (113 mg, 0.098 mmol) in amixed water (1.6 ml) and 1,4-dioxane (8.1 ml) was purged with N₂ andthen stirred at 100° C. for 1 h. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate and then washed with water. Theorganic layer was dried MgSO₄, and then filtered. The filtrate wasconcentrated to give a crude residue, which was purified by flashchromatography on a silica gel column eluting with 0 to 10% MeOH/DCM togive the desired product. LC-MS calculated for C₂₁H₁₇Cl₂N₂O₂ (M+H)⁺:m/z=399.1; found 399.1.

Step 2:(7-chloro-2-(2′-chloro-2-methyl-3′-(pyrido[3,4-b]pyrazin-8-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methanol

A vial equipped with a magnetic stir bar, was charged with(2-(3′-amino-2′-chloro-2-methyl-[1,1′-biphenyl]-3-yl)-7-chlorobenzo[d]oxazol-5-yl)methanol(31 mg, 0.078 mmol), 8-bromopyrido[3,4-b]pyrazine (33 mg, 0.16 mmol),sodium tert-butoxide (15 mg, 0.16 mmol),(±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (7.25 mg, 0.012 mmol)and tris(dibenzylideneacetone) dipalladium(0) (3.55 mg, 3.88 μmol). Themixture was bubbled by N₂ for 1 min before sealed. The reaction mixturewas heated at 100° C. for 1 h. The solution was allowed to cool to roomtemperature, then quenched by the addition of 1M HCl (1 mL), dilutedwith EtOAc and poured into sat. NaHCO₃. After extracting with EtOActhree times, the combined organic layers were washed with brine, driedover MgSO₄, and then filtered. The filtrate was concentrated. The crudeproduct was purified by flash column chromatography (0-10% MeOH in DCM)to give the desired product. LC-MS calculated for C₂₈H₂₀Cl₂N₅O₂ (M+H)⁺:m/z=528.1; found 528.2.

Step 3:(R)-1-((2-(2′-chloro-2-methyl-3′-(pyrido[3,4-b]pyrazin-8-ylamino)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 12 with(7-chloro-2-(2′-chloro-2-methyl-3′-(pyrido[3,4-b]pyrazin-8-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methanolreplacing(7-chloro-2-(2,2′-dimethyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanolin Step 1. The reaction mixture was diluted with MeOH and then purifiedby prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired productas TFA salt. LC-MS calculated for C₃₄H₂₇ClN₇O₃ (M+H)⁺: m/z=616.2; found616.2.

Example 16(R)-1-((7-chloro-2-(3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: 8-chloro-3-vinyl-1,7-naphthyridine

A mixture of 3-bromo-8-chloro-1,7-naphthyridine (PharmaBlock, cat#PBLJ2743: 1221 mg, 5.01 mmol),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (927 mg, 6.02 mmol),sodium carbonate (1329 mg, 12.54 mmol) andtetrakis(triphenylphosphine)palladium(0) (290 mg, 0.25 mmol) int-butanol (12 ml) and water (12 ml) was purged with nitrogen and sealed.It was stirred at 90° C. for 2 h. The reaction mixture was cooled toroom temperature then extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude residue was used directlyin the next step without further purification. LC-MS calculated forC₁₀H₈ClN₂ (M+H)⁺: m/z=191.0; found 191.0.

Step 2: N-(3-bromo-2-methylphenyl)-3-vinyl-1, 7-naphthyridin-8-amine

A mixture of 3-bromo-2-methylaniline (139 mg, 0.74 mmol),8-chloro-3-vinyl-1,7-naphthyridine (142 mg, 0.74 mmol) and HCl indioxane (4.0 M, 186 μL, 0.74 mmol) in t-butanol (3.7 mL) was heated at130° C. for 2 h. The reaction mixture was then cooled to roomtemperature and diluted with DCM. The reaction was quenched by aqueousNaHCO₃ solution, extracted with DCM. The organic phase was dried overMgSO₄, filtered and the filtrate was concentrated. The residue was useddirectly for next step. LC-MS calculated for C₁₇H₁₅BrN₃ (M+H)⁺:m/z=340.0; found 340.1.

Step 3: 8-(3-bromo-2-methylphenylamino)-1,7-naphthyridine-3-carbaldehyde

A vial was charged withN-(3-bromo-2-methylphenyl)-3-vinyl-1,7-naphthyridin-8-amine (281 mg,0.826 mmol), a stir bar, 1,4-dioxane (6.2 ml) and water (2.0 ml). Tothis suspension was added osmium tetroxide (4% w/w in water, 324 μl,0.041 mmol). The reaction was stirred for 5 min then sodium periodate(883 mg, 4.13 mmol) was added. After stirring at room temperature for 1h, the reaction mixture was quenched with a saturated aqueous solutionof sodium thiosulfate. The mixture was then extracted with ethylacetate, and the combined organic layers were separated, washed withbrine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The cruderesidue was used directly in the next step without further purification.LC-MS calculated for C₁₆H₁₃BrN₃O (M+H)⁺: m/z=342.0; found 342.0.

Step 4:(S)-1-((8-(3-bromo-2-methylphenylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol

A mixture of8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde (2.09g, 6.11 mmol) and (S)-pyrrolidin-3-ol (1.06 g, 12.22 mmol) in DCM (30.5ml) was stirred at room temperature for 0.5 h. Then sodiumtriacetoxyborohydride (1.94 g, 9.16 mmol) and acetic acid (0.52 ml, 9.16mmol) were added. The mixture was further stirred at room temperaturefor 1 h. The reaction mixture was quenched by NH₄OH aqueous solution andextracted with DCM. The organic phase was combined and dried over MgSO₄,then filtered. The filtrate was concentrated and purified by columnchromatography (0-8% MeOH in DCM) to give the desired product. LC-MScalculated for C₂₀H₂₂BrN₄O (M+H)⁺: m/z=413.0; found 413.1.

Step 5:(S)-1-((8-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol

A mixture of(S)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol(462 mg, 1.12 mmol),(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol(673 mg, 1.23 mmol), sodium carbonate (296 mg, 2.79 mmol) andtetrakis(triphenylphosphine)palladium(0) (129 mg, 0.112 mmol) in water(1.9 mL) and 1,4-dioxane (9.3 mL) was purged with N₂ and then stirred at100° C. for 4 h. The reaction mixture was cooled to room temperature,diluted with ethyl acetate and then washed with H₂O. The organic layerwas dried MgSO₄ and filtered. The filtrate was concentrated to give acrude residue, which was purified by flash chromatography on a silicagel column eluting with 0 to 12% MeOH/DCM to give the desired product.LC-MS calculated for C₃₅H₃₃ClN₅O₃ (M+H)⁺: m/z=606.2; found 606.4.

Step 6:(S)-7-chloro-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-carbaldehyde

A suspension of(S)-1-((8-((3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol(35 mg, 0.058 mmol) and manganese dioxide (100 mg, 1.16 mmol) in DCM(580 μl) was stirred at 45° C. for 15 min. The reaction mixture wascooled to room temperature, filtered through a short pad of celite andthen concentrated to yield a crude residue, which was used directlywithout further purification. LC-MS calculated for C₃₅H₃₁ClN₅O₃ (M+H)⁺:m/z=604.2; found 604.4.

Step 7:(R)-1-((7-chloro-2-(3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of(S)-7-chloro-2-(3′-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-5-carbaldehyde(31 mg, 0.051 mmol), (R)-pyrrolidine-3-carboxylic acid (17.7 mg, 0.154mmol) and triethylamine (21.5 μL, 0.154 mmol) in DCM (500 μL) wasstirred at room temperature for 2 h. Then sodium triacetoxyborohydride(32.6 mg, 0.154 mmol) and acetic acid (8.81 μL, 0.154 mmol) were added.The mixture was further stirred at room temperature for 1 h. Thereaction mixture was diluted with MeOH and then purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₄₀H₄₀ClN₆O₄ (M+H)⁺: m/z=703.3; found 703.3.¹H NMR (400 MHz, 330K, CD₃CN) δ 9.11 (d, J=2.0 Hz, 1H), 8.52 (d, J=2.1Hz, 1H), 8.19 (dd, J=7.9, 1.5 Hz, 1H), 7.93-7.78 (m, 3H), 7.66 (d, J=1.5Hz, 1H), 7.57-7.41 (m, 3H), 7.29-7.18 (m, 2H), 4.63-4.55 (m, 3H), 4.44(s, 2H), 3.58-3.34 (m, 9H), 2.53 (s, 3H), 2.45-2.28 (m, 3H), 2.10-2.05(m, 4H).

Example 17(S)-1-((7-chloro-2-(3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 16 with (S)-pyrrolidine-3-carboxylic acid replacing(R)-pyrrolidine-3-carboxylic acid in Step 7. The reaction was dilutedwith MeOH and then purified by prep-HPLC (pH=10,acetonitrile/water+NH₄OH) to give the desired product. LC-MS calculatedfor C₄₀H₄₀ClN₆O₄ (M+H)⁺: m/z=703.3; found 703.3.

Example 18(R)-1-((7-chloro-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 16 with (R)-pyrrolidin-3-ol replacing (S)-pyrrolidin-3-ol inStep 4. For the last step, the reaction mixture was diluted with MeOHand then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to givethe desired product as TFA salt. LC-MS calculated for C₄₀H₄₀ClN₆O₄(M+H)⁺: m/z=703.3; found 703.3. ¹H NMR (600 MHz, DMSO) δ 10.84-10.49 (m,1H), 10.43-10.21 (m, 1H), 9.07 (s, 1H), 8.52 (s, 1H), 8.16 (dd, J=8.0,1.4 Hz, 2H), 8.03 (d, J=1.5 Hz, 2H), 7.79 (d, J=1.4 Hz, 1H), 7.57 (t,J=7.7 Hz, 1H), 7.46 (dd, J=7.7, 1.4 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H),7.23 (d, J=5.9 Hz, 1H), 7.05 (s, 1H), 5.52 (br, 1H), 4.84-4.36 (m, 5H),3.76-3.07 (m, 9H), 2.48 (s, 3H), 2.44-2.15 (m, 3H), 2.06 (s, 3H),2.03-1.80 (m, 1H).

Example 19(S)-1-((7-chloro-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 16 with (R)-pyrrolidin-3-ol replacing (S)-pyrrolidin-3-ol inStep 4 and (S)-pyrrolidine-3-carboxylic acid replacing(R)-pyrrolidine-3-carboxylic acid in the Step 7. For the last step, thereaction mixture was diluted with MeOH and then purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as TFA salt.LC-MS calculated for C₄₀H₄₀ClN₆O₄ (M+H)⁺: m/z=703.3; found 703.3.

Example 20(S)-3-((7-chloro-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methylamino)propanoicAcid

This compound was prepared using similar procedures as described forExample 16 with 3-aminopropanoic acid replacing(R)-pyrrolidine-3-carboxylic acid in Step 7. The reaction mixture wasdiluted with MeOH and then purified by prep-HPLC (pH=10,acetonitrile/water+NH₄OH) to give the desired product. LC-MS calculatedfor C₃₈H₃₈ClN₆O₄ (M+H)⁺: m/z=677.3; found 677.3.

Example 21(S)-3-(((7-chloro-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)(methyl)amino)propanoicAcid

This compound was prepared using similar procedures as described forExample 16 with 3-(methylamino)propanoic acid replacing(R)-pyrrolidine-3-carboxylic acid in Step 7. The reaction mixture wasdiluted with MeOH and then purified by prep-HPLC (pH=10,acetonitrile/water+NH₄OH) to give the desired product. LC-MS calculatedfor C₃₉H₄₀ClN₆O₄ (M+H)⁺: m/z=691.3; found 691.2.

Example 22(S)-1-((7-chloro-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylicAcid

This compound was prepared using similar procedures as described forExample 16 with piperidine-4-carboxylic acid replacing(R)-pyrrolidine-3-carboxylic acid in Step 7. The reaction was dilutedwith MeOH and then purified by prep-HPLC (pH=10,acetonitrile/water+NH₄OH) to give the desired product. LC-MS calculatedfor C₄₁H₄₂ClN₆O₄ (M+H)⁺: m/z=717.3; found 717.3.

Example 23(S)-1-((7-chloro-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 16 with azetidine-3-carboxylic acid replacing(R)-pyrrolidine-3-carboxylic acid in Step 7. The reaction was dilutedwith MeOH and then purified by prep-HPLC (pH=10,acetonitrile/water+NH₄OH) to give the desired product. LC-MS calculatedfor C₃₉H₃₈ClN₆O₄ (M+H)⁺: m/z=689.3; found 689.3.

Example 24(R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:(R)-1-((8-(3-bromo-2-methylphenylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol

A mixture of8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde(Example 16, Step 3:102 mg, 0.298 mmol) and (R)-pyrrolidin-3-ol (51.9mg, 0.596 mmol) in DCM (1490 μl) was stirred at room temperature for 0.5h. Then sodium triacetoxyborohydride (95 mg, 0.447 mmol) and acetic acid(25.0 μl, 0.447 mmol) were added. The mixture was further stirred atroom temperature for 1 h. The reaction mixture was quenched by NH₄OHaqueous solution then extracted with DCM. The organic phase was combinedand dried over MgSO₄, then filtered. The filtrate was concentrated andused directly in the next step without further purification. LC-MScalculated for C₂₀H₂₂BrN₄O (M+H)⁺: m/z=413.1; found 413.1.

Step 2:(R)-1-((8-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol

A mixture of(R)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol(419 mg, 1.01 mmol),(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol(Example 1, Step 5: 611 mg, 1.12 mmol), sodium carbonate (269 mg, 2.53mmol) and tetrakis(triphenylphosphine)palladium(0) (117 mg, 0.101 mmol)in water (1.7 mL) and 1,4-dioxane (8.4 mL) was purged with N₂ and thenstirred at 100° C. for 4 h. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate and then washed with H₂O. Theorganic layer was dried over MgSO₄ and filtered. The filtrate wasconcentrated to give a crude residue, which was purified by flashchromatography on a silica gel column eluting with 0 to 15% MeOH/DCM togive the desired product. LC-MS calculated for C₃₅H₃₃ClN₅O₃ (M+H)⁺:m/z=606.2; found 606.4.

Step 3:(R)-5-(hydroxymethyl)-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile

A mixture of(R)-1-((8-((3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol(79 mg, 0.13 mmol),[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (10.4 mg, 0.013 mmol), potassiumhexacyanoferrate(II) trihydrate (55.1 mg, 0.130 mmol) and potassiumacetate (2.6 mg, 0.026 mmol) in 1,4-dioxane (650 μl) and water (650 μl)was stirred and heated at 100° C. for 4 h. After cooling to roomtemperature, the reaction mixture was diluted with EtOAc and water,extracted with EtOAc. The combined organic phase was dried over MgSO₄,and then filtered. The filtrate was concentrated. The crude material waspurified by column chromatography (0-8% MeOH in DCM) to give the desiredproduct. LC-MS calculated for C₃₆H₃₃N₆O₃ (M+H)⁺: m/z=597.3; found 597.2.

Step 4:(R)-5-formyl-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile

A suspension of(R)-5-(hydroxymethyl)-2-(3′-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile(72 mg, 0.12 mmol) and manganese dioxide (231 mg, 2.65 mmol) in DCM (1.2mL) was stirred at 45° C. for 25 min. The reaction mixture was cooled toroom temperature, filtered through a short pad of celite and thenconcentrated to yield a crude residue, which was used directly in thenext step without further purification. LC-MS calculated for C₃₆H₃₁N₆O₃(M+H)⁺: m/z=595.2; found 595.2.

Step 5:(R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of(R)-5-formyl-2-(3′-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile(72 mg, 0.12 mmol), (R)-pyrrolidine-3-carboxylic acid (27.9 mg, 0.242mmol) and triethylamine (34 μl, 0.24 mmol) in DCM (800 μl) was stirredat room temperature for 2 h. Then sodium triacetoxyborohydride (38.5 mg,0.182 mmol) and acetic acid (10.5 μl, 0.18 mmol) was added. The mixturewas further stirred at room temperature for 1 h. The reaction mixturewas diluted with MeOH and then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₄₁H₄₀N₇O₄ (M+H)⁺: m/z=694.3; found 694.3. ¹H NMR (500MHz, DMSO) δ 9.07 (s, 1H), 8.55-8.48 (m, 1H), 8.40 (d, J=1.5 Hz, 1H),8.25-8.10 (m, 3H), 8.04 (d, J=5.8 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.48(dd, J=7.6, 1.4 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.23 (d, J=6.0 Hz, 1H),7.06 (d, J=7.3 Hz, 1H), 4.86-4.36 (m, 5H), 3.88-3.00 (m, 9H), 2.49 (s,3H), 2.42-2.15 (m, 2H), 2.06 (s, 3H), 2.02-1.80 (m, 2H).

Example 25(S)-1-((7-cyano-2-(3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared similar procedures as described for Example24 with (S)-pyrrolidin-3-ol replacing (R)-pyrrolidin-3-ol in Step 1 and(S)-pyrrolidine-3-carboxylic acid replacing (R)-pyrrolidine-3-carboxylicacid in Step 5. The reaction was diluted with MeOH and then purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₄₁H₄₀N₇O₄ (M+H)⁺: m/z=694.3; found694.3. ¹H NMR (600 MHz, DMSO) δ 9.14 (s, 1H), 8.58 (s, 1H), 8.40 (d,J=1.6 Hz, 1H), 8.20 (dd, J=8.1, 1.3 Hz, 1H), 8.14 (d, J=1.6 Hz, 1H),8.02-7.87 (m, 2H), 7.60 (t, J=7.7 Hz, 1H), 7.52-7.43 (m, 2H), 7.27 (d,J=6.5 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 4.85-4.39 (m, 5H), 3.79-3.09 (m,9H), 2.50 (s, 3H), 2.44-2.07 (m, 3H), 2.03 (s, 3H), 1.94-1.83 (m, 1H).

Example 26(R)-1-((7-cyano-2-(3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 24 with (S)-pyrrolidin-3-ol replacing (R)-pyrrolidin-3-ol inStep 1. The reaction mixture was diluted with MeOH and then purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₄₁H₄₀N₇O₄ (M+H)⁺: m/z=694.3; found694.3. ¹H NMR (500 MHz, DMSO) δ 9.13 (s, 1H), 8.57 (s, 1H), 8.42-8.35(m, 1H), 8.19 (d, J=7.8 Hz, 1H), 8.13 (d, J=1.1 Hz, 1H), 8.03-7.86 (m,2H), 7.58 (t, J=7.7 Hz, 1H), 7.46 (dd, J=14.9, 7.2 Hz, 2H), 7.26 (d,J=6.1 Hz, 1H), 7.16 (d, J=6.8 Hz, 1H), 4.81-4.40 (m, 5H), 3.79-3.07 (m,9H), 2.49 (s, 3H), 2.28-1.87 (m, 4H), 2.02 (s, 3H).

Example 27(S)-1-((7-cyano-2-(3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicAcid

This compound was prepare using similar procedures as described orExample 24 with (S)-pyrrolidin-3-ol replacing (R)-pyrrolidin-3-ol inStep 1 and (S)-piperidine-2-carboxylic acid replacing(R)-pyrrolidine-3-carboxylic acid in Step 5. The reaction mixture wasdiluted with MeOH and then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₄₂H₄₂N₇O₄ (M+H)⁺: m/z=708.3; found 708.3. ¹H NMR (600MHz, DMSO) δ 9.10 (s, 1H), 8.54 (s, 1H), 8.30 (s, 1H), 8.20 (d, J=7.9Hz, 1H), 8.04 (s, 2H), 7.95 (m, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.48 (d,J=7.5 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.25 (d, J=5.4 Hz, 1H), 7.14 (d,J=8.4 Hz, 1H), 4.81-4.57 (m, 3H), 4.55-4.28 (m, 2H), 4.03 (s, 1H),3.73-2.96 (m, 6H), 2.49 (s, 3H), 2.36-2.12 (m, 2H), 2.03 (s, 3H),1.99-1.43 (m, 6H).

Example 28(S)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 24 with (S)-pyrrolidine-3-carboxylic acid replacing(R)-pyrrolidine-3-carboxylic acid in Step 5. The reaction mixture wasdiluted with MeOH and then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₄₁H₄₀N₇O₄ (M+H)⁺: m/z=694.3; found 694.3. ¹H NMR (500MHz, DMSO) δ 9.09 (s, 1H), 8.53 (s, 1H), 8.40 (d, J=1.6 Hz, 1H), 8.20(dd, J=8.0, 1.4 Hz, 1H), 8.17-8.06 (m, 2H), 8.01 (d, J=6.8 Hz, 1H), 7.59(t, J=7.7 Hz, 1H), 7.48 (dd, J=7.7, 1.4 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H),7.24 (d, J=6.0 Hz, 1H), 7.09 (d, J=7.7 Hz, 1H), 4.82-4.37 (m, 5H),3.77-3.06 (m, 9H), 2.50 (s, 3H), 2.43-1.82 (m, 4H), 2.06 (s, 3H).

Example 29(R)-1-((7-chloro-2-(2′-chloro-3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: 8-chloro-3-vinyl-1,7-naphthyridine

A mixture of 3-bromo-8-chloro-1,7-naphthyridine (PharmaBlock, cat#PBLJ2743: 770 mg, 3.16 mmol),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (584 mg, 3.79 mmol),sodium carbonate (838 mg, 7.91 mmol) andtetrakis(triphenylphosphine)palladium(0) (183 mg, 0.158 mmol) int-butanol (8 ml) and water (8 ml) was purged with nitrogen and sealed.It was stirred at 80° C. for 2 h. The reaction mixture was cooled thenextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over MgSO₄, and filtered. The filtrate wasconcentrated under reduced pressure. The crude residue was used directlyin the next step without further purification. LC-MS calculated forC₁₀H₈ClN₂ (M+H)⁺: m/z=191.0; found 191.0.

Step 2: N-(3-bromo-2-chlorophenyl)-3-vinyl-1,7-naphthyridin-8-amine

A mixture of 3-bromo-2-chloroaniline (536 mg, 2.59 mmol),8-chloro-3-vinyl-1,7-naphthyridine (471 mg, 2.47 mmol) and HCl indioxane (618 μl, 2.47 mmol) in t-butanol (12.4 mL) was heated at 120° C.for 2 h. The reaction mixture was cooled to room temperature, dilutedwith DCM then quenched by aqueous NaHCO₃ solution and extracted withDCM. The organic phase was dried over MgSO₄, filtered and the filtratewas concentrated. The residue was used directly in the next step withoutfurther purification. LC-MS calculated for C₁₆H₁₂BrClN₃ (M+H)⁺:m/z=360.0; found 360.0.

Step 3: 8-(3-bromo-2-chlorophenylamino)-1,7-naphthyridine-3-carbaldehyde

To the solution ofN-(3-bromo-2-chlorophenyl)-3-vinyl-1,7-naphthyridin-8-amine (135 mg,0.374 mmol) in 1,4-dioxane (2.8 mL) and water (0.9 mL) was added osmiumtetroxide (4% w/w in water, 147 μl, 0.019 mmol). The mixture was stirredat room temperature for 5 min then sodium periodate (400 mg, 1.872 mmol)was added. After stirring at room temperature for 1 h, the reactionmixture was quenched with a saturated aqueous solution of sodiumthiosulfate. The mixture was then extracted with ethyl acetate, and thecombined organic layers were separated, washed with brine, dried overNa₂SO₄, filtered, and concentrated in vacuo. The crude residue was useddirectly in the next step without further purification. LC-MS calculatedfor C₁₅H₁₀BrClN₃O (M+H)⁺: m/z=362.0; found 362.0.

Step 4:(S)-1-((8-(3-bromo-2-chlorophenylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol

A mixture of8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridine-3-carbaldehyde (384mg, 1.06 mmol) and (S)-pyrrolidin-3-ol (185 mg, 2.12 mmol) in DCM (5.3mL) was stirred at room temperature for 0.5 h. Then sodiumtriacetoxyborohydride (337 mg, 1.59 mmol) and acetic acid (91 μl, 1.59mmol) were added. The mixture was further stirred at room temperaturefor 1 h. The reaction mixture was quenched by NH₄OH aqueous solution andextracted with DCM. The organic phase was combined and dried over MgSO₄,then filtered. The filtrate was concentrated and the residue waspurified by column chromatography on a silica gel column eluting with 0to 8% MeOH/DCM to give the desired product. LC-MS calculated forC₁₉H₁₉BrClN₄O (M+H)⁺: m/z=433.0; found 433.0.

Step 5:(S)-1-((8-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol

A mixture of(S)-1-((8-(3-bromo-2-chlorophenylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol(10.3 mg, 0.024 mmol),(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol(Example 1, Step 5: 9.5 mg, 0.024 mmol), sodium carbonate (6.30 mg,0.059 mmol) and tetrakis(triphenylphosphine) palladium(0) (2.75 mg,2.377 μmol) in water (40 μl) and 1,4-dioxane (200 μl) was purged with N₂and then stirred at 100° C. for 1 h. The reaction mixture was cooled toroom temperature, diluted with ethyl acetate and then washed with H₂O.The organic layer was dried MgSO₄ and filtered. The filtrate wasconcentrated to give a crude residue, which was purified by flashchromatography on a silica gel column eluting with 0 to 15% MeOH/DCM togive the desired product. LC-MS calculated for C₃₄H₃₀Cl₂N₅O₃ (M+H)⁺:m/z=626.2; found 626.2.

Step 6:(S)-7-chloro-2-(2′-chloro-3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)benzo[d]oxazole-5-carbaldehyde

A suspension of(S)-1-((8-((2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol(4.9 mg, 7.8 μmol) and manganese dioxide (17 mg, 0.20 mmol) in DCM (80μl) was stirred at 45° C. for 15 min. The reaction mixture was filteredthrough a short pad of celite and then concentrated to yield a cruderesidue, which was used directly without further purification. LC-MScalculated for C₃₄H₂₈Cl₂N₅O₃ (M+H)⁺: m/z=624.2; found 624.3.

Step 7:(R)-1-((7-chloro-2-(2′-chloro-3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of(S)-7-chloro-2-(2′-chloro-3′-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2-methyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-5-carbaldehyde(4.5 mg, 7.2 μmol), triethylamine (3.0 μl, 0.022 mmol) and(R)-pyrrolidine-3-carboxylic acid (2.5 mg, 0.022 mmol) in DCM (75 μl)was stirred at rt for 2 h. Then sodium triacetoxyborohydride (4.5 mg,0.022 mmol) and acetic acid (1.2 μl, 0.022 mmol) were added. The mixturewas further stirred at rt for 1 h. The reaction was diluted with MeOHand then purified by prep-HPLC (pH=10, acetonitrile/water+NH₄OH) to givethe desired product. LC-MS calculated for C₃₉H₃₇Cl₂N₆O₄ (M+H)⁺:m/z=723.2; found 723.2.

Example 30(R)-1-((2-(2′-chloro-3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:(S)-2-(2′-chloro-3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrile

A mixture of(S)-1-((8-((2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol(Example 29, Step 5: 114 mg, 0.182 mmol),[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (14.4 mg, 0.018 mmol), potassiumhexacyanoferrate(II) trihydrate (77 mg, 0.18 mmol) and potassium acetate(3.6 mg, 0.036 mmol) in 1,4-dioxane (910 μl) and water (910 μl) wasstirred and heated at 100° C. for 1 h. After cooling to roomtemperature, the reaction mixture was diluted with EtOAc and water,extracted with EtOAc. The combined organic phase was dried over MgSO₄,and then filtered. The filtrate was concentrated. The crude material waspurified by column chromatography (0-8% MeOH in DCM) to give the desiredproduct. LC-MS calculated for C₃₅H₃₀ClN₆O₃ (M+H)⁺: m/z=617.2; found617.4.

Step 2:(S)-2-(2′-chloro-3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile

A suspension of(S)-2-(2′-chloro-3′-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2-methyl-[1,1′-biphenyl]-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrile(64 mg, 0.104 mmol) and manganese dioxide (198 mg, 2.28 mmol) in DCM(1.0 mL) was stirred at 45° C. for 15 min. The reaction was filteredthrough a short pad of celite and then concentrated to yield a cruderesidue, which was used directly without further purification. LC-MScalculated for C₃₅H₂₈ClN₆O₃ (M+H)⁺: m/z=615.2; found 615.2.

Step 3:(R)-1-((2-(2′-chloro-3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of(S)-2-(2′-chloro-3′-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2-methyl-[1,1′-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile(53.2 mg, 0.086 mmol), (R)-pyrrolidine-3-carboxylic acid (29.9 mg, 0.259mmol) and triethylamine (36 μl, 0.259 mmol) in DCM (580 μl) was stirredat rt for 2 h. Then sodium triacetoxyborohydride (55.0 mg, 0.259 mmol)and acetic acid (14.8 μl, 0.259 mmol) were added. The mixture wasfurther stirred at rt for 1 h. The reaction was diluted with MeOH andthen purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as TFA salt. LC-MS calculated for C₄₀H₃₇ClN₇O₄ (M+H)⁺:m/z=714.3; found 714.3. ¹H NMR (600 MHz, DMSO) δ 10.00 (s, 1H),9.12-9.06 (m, 1H), 9.05-9.01 (m, 1H), 8.57 (s, 1H), 8.40 (d, J=1.6 Hz,1H), 8.30-8.19 (m, 2H), 8.14 (d, J=1.6 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H),7.59-7.52 (m, 2H), 7.44-7.34 (m, 1H), 7.11 (dd, J=7.7, 1.5 Hz, 1H),4.82-4.36 (m, 5H), 3.73-3.07 (m, 9H), 2.51 (s, 3H), 2.44-1.82 (m, 4H).

Example 31(R)-1-((2-(2′-chloro-2-methyl-3′-(3-((2-oxooxazolidin-3-yl)methyl)-1,7-naphthyridin-8-ylamino)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:2-((8-(3-bromo-2-chlorophenylamino)-1,7-naphthyridin-3-yl)methylamino)ethanol

This compound was prepared using similar procedures as described forExample 29 with 2-aminoethanol replacing (S)-pyrrolidin-3-ol in Step 4.LC-MS calculated for C₁₇H₁₇BrClN₄O (M+H)⁺: m/z=407.0; found 407.0.

Step 2:3-((8-(3-bromo-2-chlorophenylamino)-1,7-naphthyridin-3-yl)methyl)oxazolidin-2-one

To a solution of2-(((8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridin-3-yl)methyl)amino)ethan-1-ol(30 mg, 0.075 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (17.8 μl,0.12 mmol) in DCM (750 μl) was added 1,1′-carbonyldiimidazole (15.7 mg,0.10 mmol). The mixture was stirred at room temperature for 30 min. Thereaction was concentrated and purified by column chromatography (0-5%MeOH in DCM). LC-MS calculated for C₁₈H₁₅BrClN₄O₂ (M+H)⁺: m/z=433.0;found 433.1.

Step 3:(R)-1-((2-(2′-chloro-2-methyl-3′-(3-((2-oxooxazolidin-3-yl)methyl)-1,7-naphthyridin-8-ylamino)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 24, Step 2-5 with3-((8-(3-bromo-2-chlorophenylamino)-1,7-naphthyridin-3-yl)methyl)oxazolidin-2-onereplacing(R)-1-((8-(3-bromo-2-methylphenylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-olin Step 2. The reaction was diluted with MeOH and then purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₃₉H₃₃ClN₇O₅ (M+H)⁺: m/z=714.2; found714.2.

Example 32(S)-1-((7-chloro-2-(2′-chloro-3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 29 with (S)-pyrrolidine-3-carboxylic acid replacing(R)-pyrrolidine-3-carboxylic acid in Step 7. The reaction was dilutedwith MeOH and then purified by prep-HPLC (pH=2, acetonitrile/water+TFA)to give the desired product as TFA salt. LC-MS calculated forC₃₉H₃₇Cl₂N₆O₄ (M+H)⁺: m/z=723.2; found 723.2.

Example 33(S)-1-((2-(2′-chloro-3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 30 with (S)-pyrrolidine-3-carboxylic acid replacing(R)-pyrrolidine-3-carboxylic acid in Step 3. For the last step, thereaction was diluted with MeOH and then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₄₀H₃₇ClN₇O₄ (M+H)⁺: m/z=714.3; found 714.3.

Example 34(R)-1-((2-(2′-chloro-3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 30 with (R)-3-methylpyrrolidine-3-carboxylic acid (J&W Pharmlab,#75R0495) replacing (R)-pyrrolidine-3-carboxylic acid in Step 3. For thelast step, the reaction was diluted with MeOH and then purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₄₁H₃₉ClN₇O₄ (M+H)⁺: m/z=728.3; found728.3.

Example 35(S)-1-((7-cyano-2-(3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-2-carboxylicAcid

This compound was prepared using similar procedures as described forExample 24 with (S)-pyrrolidin-3-ol replacing (R)-pyrrolidin-3-ol inStep 1 and (S)-pyrrolidine-2-carboxylic acid replacing(R)-pyrrolidine-3-carboxylic acid in Step 5. The reaction was dilutedwith MeOH and then purified by prep-HPLC (pH=10,acetonitrile/water+NH₄OH) to give the desired product. LC-MS calculatedfor C₄₁H₄₀N₇O₄ (M+H)⁺: m/z=694.3; found 694.3.

Example 36(S)-1-((7-cyano-2-(3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: tert-butyl1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

A solution of 1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine(Accela, cat #SY032476: 2.0 g, 14.58 mmol), (Boc)₂O (3.38 mL, 14.58mmol) in dichloromethane (60 mL) was stirred at room temperature for 1h. The reaction was quenched with saturated aqueous NaHCO₃ solution, andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The crude product was used for next step without furtherpurification. LCMS calculated for C₁₂H₂₀N₃O₂ (M+H)⁺: m/z=238.2; found238.2.

Step 2: 5-tert-butyl 2-methyl1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-2,5(4H)-dicarboxylate

n-Butyllithium in hexanes (2.5 M, 7.00 mL, 17.49 mmol) was added to acold (−78° C.) solution of the crude product from Step 1 intetrahydrofuran (60.0 mL). The reaction mixture was stirred at −78° C.for 10 min prior to the addition of methyl chloroformate (1.7 mL, 21.9mmol). After being stirred at −78° C. for 30 min, the reaction was thenquenched with saturated aqueous NaHCO₃ solution, and extracted withethyl acetate, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by flash chromatography on asilica gel column eluting with 0 to 100% ethyl acetate in hexanes toafford the desired product. LCMS calculated for C₁₄H₂₂N₃O₄ (M+H)⁺:m/z=296.2; found 296.3.

Step 3: tert-butyl2-(3-bromo-2-methylphenylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

Potassium tert-butoxide in THF (1.0 M, 3.39 mL, 3.39 mmol) was added toa solution of 5-tert-butyl 2-methyl1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-2,5(4H)-dicarboxylate(500 mg, 1.69 mmol) and 3-bromo-2-methylaniline (1.69 mmol) intetrahydrofuran (12.0 mL). After being stirred at room temperature for 1h, the reaction mixture was quenched with water, and extracted withethyl acetate. The combined organic layers were washed with brine, driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel columneluting with 50% ethyl acetate in hexanes to afford the desired product(720 mg, 95%). LCMS calculated for C₂₀H₂₆BrN₄O₃ (M+H)⁺: m/z=449.1; found449.1.

Step 4: tert-butyl2-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

A mixture of tert-butyl2-((3-bromo-2-methylphenyl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate(400 mg, 0.89 mmol),(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol(Example 1, Step 5: 356 mg, 0.89 mmol),tetrakis(triphenylphosphine)palladium(0) (103 mg, 0.089 mmol) and sodiumcarbonate (236 mg, 2.23 mmol) in water (1.5 mL) and 1,4-dioxane (7.5 mL)was purged with nitrogen and then stirred at 100° C. for 3 h. Afterbeing cooled to room temperature, the reaction mixture was extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel columneluting with 0 to 50% ethyl acetate in hexanes to afford the desiredproduct (350 mg, 61%). LC-MS calculated for C₃₅H₃₇ClN₅O₅ (M+H)⁺:m/z=642.3; found 642.3.

Step 5: tert-butyl2-(3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

A mixture of tert-butyl2-((3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate(350 mg, 0.545 mmol),[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (43.3 mg, 0.055 mmol), potassiumhexacyanoferrate(II) trihydrate (230 mg, 0.545 mmol) and potassiumacetate (10.70 mg, 0.109 mmol) in 1,4-dioxane (4.5 mL) and water (4.5mL) was purged with nitrogen and then stirred at 100° C. for 1 h. Afterbeing cooled to rt, the reaction was extracted with ethyl acetate. Thecombined organic phases was dried over Na₂SO₄ and concentrated underreduced pressure. The crude was used directly for next step withoutfurther purification. LC-MS calculated for C₃₆H₃₇N₆O₅ (M+H)⁺: m/z=633.4;found 633.3.

Step 6: tert-butyl2-(3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

A suspension of tert-butyl2-((3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate(345 mg, 0.545 mmol) and manganese dioxide (948 mg, 10.91 mmol) indichloromethane (5.0 mL) was stirred at 45° C. for 30 min. The reactionwas filtered through a short pad of celite and then concentrated toyield a crude residue, which was used directly without furtherpurification. LC-MS calculated for C₃₆H₃₅N₆O₅ (M+H)⁺: m/z=631.3; found631.3.

Step 7:(S)-1-((7-cyano-2-(2,2′-dimethyl-3′-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of tert-butyl2-((3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate(200 mg, 0.317 mmol) and (S)-pyrrolidine-3-carboxylic acid (110 mg,0.951 mmol) in dichloromethane (3.0 mL) was stirred at room temperaturefor 2 h. Then sodium triacetoxyborohydride (202 mg, 0.951 mmol) andacetic acid (54.5 μl, 0.951 mmol) was added. After being stirred at 50°C. for 1 h, 2 N HCl in water (0.2 mL) was added, and the reaction wasstirred at room temperature for 1 h. The reaction mixture wasconcentrated, and purified via pH 2 preparative HPLC (MeCN/water withTFA) to give the desired product as TFA salt. LC-MS calculated forC₃₆H₃₆N₇O₄ (M+H)⁺: m/z=630.3; found 630.4.

Step 8:(S)-1-((7-cyano-2-(3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Sodium triacetoxyborohydride (32.7 mg, 0.154 mmol) was added to asolution of(S)-1-((7-cyano-2-(2,2′-dimethyl-3′-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid, 3TFA (50 mg, 0.051 mmol) and 37 wt. % formaldehyde in water (38.3μL, 0.515 mmol) in THF (0.5 mL). The reaction mixture was stirred atroom temperature for 1 h, then diluted with MeOH, and purified via pH 2preparative HPLC (MeCN/water with TFA) to give the desired product asTFA salt. ¹H NMR (400 MHz, CD₃CN) δ 9.24 (s, 1H), 8.27-8.22 (m, 2H),7.98-7.95 (m, 1H), 7.54 (dd, J=7.7, 7.7 Hz, 1H), 7.43 (dd, J=7.7, 1.4Hz, 1H), 7.37 (dd, J=7.7, 7.7 Hz, 1H), 7.07 (dd, J=7.7, 1.4 Hz, 1H),4.49 (d, J=13.5 Hz, 1H), 4.45 (d, J=13.5 Hz, 1H), 4.30-4.15 (m, 2H),3.98 (s, 3H), 3.67-3.45 (m, 4H), 3.44-3.26 (m, 3H), 3.11-3.00 (m, 2H),2.96 (s, 3H), 2.50 (s, 3H), 2.43-2.20 (m, 2H), 2.06 (s, 3H). LC-MScalculated for C₃₇H₃₈N₇O₄ (M+H)⁺: m/z=644.3; found 644.3.

Example 37(S)-1-((7-cyano-2-(3′-(5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Sodium triacetoxyborohydride (6.54 mg, 0.031 mmol) were added to asolution of(S)-1-((7-cyano-2-(2,2′-dimethyl-3′-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid, 3TFA (Example 36, Step 7; 10 mg, 10.29 μmol) and acetaldehyde(1.360 mg, 0.031 mmol) in THF (0.5 mL). The reaction was stirred at roomtemperature for 1 h, then diluted with MeOH, and purified via pH 2preparative HPLC (MeCN/water with TFA) to give the desired product asTFA salt. LC-MS calculated for C₃₈H₄₀N₇O₄ (M+H)⁺: m/z=658.3; found658.4.

Example 38(S)-1-((7-cyano-2-(3′-(5-isopropyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A suspension of(S)-1-((7-cyano-2-(2,2′-dimethyl-3′-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid, 3TFA (Example 36, Step 7; 10 mg, 10.27 μmol), 2-iodopropane (5.24mg, 0.031 mmol), and potassium carbonate (7.1 mg, 0.051 mmol) in DMF(0.1 mL) was stirred at 90° C. for 1 h. The reaction was diluted withMeOH, and purified via pH 2 preparative HPLC (MeCN/water with TFA) togive the desired product as TFA salt. LC-MS calculated for C₃₉H₄₂N₇O₄(M+H)⁺: m/z=672.3; found 672.3.

Example 39(S)-1-((7-cyano-2-(3′-(5-cyclopropyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A suspension of(S)-1-((7-cyano-2-(2,2′-dimethyl-3′-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid, 3TFA (Example 36, Step 7; 10 mg, 10.27 μmol), bromocyclopropane(12.42 mg, 0.103 mmol), potassium iodide (5.11 mg, 0.031 mmol) andpotassium carbonate (7.1 mg, 0.051 mmol) in DMF (50 μL) was stirred at90° C. for 5 h. The reaction was diluted with MeOH, and purified via pH2 preparative HPLC (MeCN/water with TFA) to give the desired product asTFA salt. LC-MS calculated for C₃₉H₄₀N₇O₄ (M+H)⁺: m/z=670.3; found670.4.

Example 40(S)-1-((7-cyano-2-(3′-(5-(3,3-difluorocyclobutyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A suspension of(S)-1-((7-cyano-2-(2,2′-dimethyl-3′-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid, 3TFA (Example 36, Step 7; 10 mg, 10.27 μmol),3-bromo-1,1-difluorocyclobutane (5.27 mg, 0.031 mmol), potassium iodide(5.11 mg, 0.031 mmol) and potassium carbonate (7.10 mg, 0.051 mmol) inDMF (0.2 mL) was stirred at 90° C. for 1 h. The reaction was dilutedwith MeOH, and purified via pH 2 preparative HPLC (MeCN/water with TFA)to give the desired product as TFA salt. LC-MS calculated forC₄₀H₄₀F₂N₇O₄ (M+H)⁺: m/z=720.3; found 720.4.

Example 41(S)-1-((7-cyano-2-(3′-(5-((S)-2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A solutionof(S)-1-((7-cyano-2-(2,2′-dimethyl-3′-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid, 3TFA (Example 36, Step 7; 10 mg, 10.29 μmol),(S)-2-((tert-butyldimethylsilyl)oxy)propanal (5.81 mg, 0.031 mmol) andHünig's base (5.39 μL, 0.031 mmol) in THF (0.2 mL) was stirred at roomtemperature for 1 h. Sodium triacetoxyborohydride (6.54 mg, 0.031 mmol)was added. After being stirred at room temperature for 2 h, 2 N HClsolution in water (0.2 mL) was added, and the reaction was stirred at50° C. for 30 min. The reaction mixture was diluted with MeOH, andpurified via pH 2 preparative HPLC (MeCN/water with TFA) to give thedesired product as TFA salt. LC-MS calculated for C₃₉H₄₂N₇O₅ (M+H)⁺:m/z=688.3; found 688.4.

Example 423-(((7-chloro-2-(3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)(methyl)amino)propanoic Acid

Step 1:N-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide

To a solution of tert-butyl2-((3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate(Example 36, Step 4; 121 mg, 0.188 mmol) in DCM (1.9 ml) was slowlyadded trifluoroacetic acid (360 μl, 4.7 mmol) at room temperature. Themixture was stirred at this temperature for 1 h. Then the mixture wasconcentrated and redissolved in DCM, washed by sat. NaHCO₃ aq. solution,water. The organic phase was dried over MgSO₄, and then filtered. Thefiltrate was concentrated to give a crude material, which was useddirectly for next step. LC-MS calculated for C₃₀H₂₉ClN₅O₃ (M+H)⁺:m/z=542.2; found 542.2.

Step 2:N-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide

A mixture ofN-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamideand paraformaldehyde (8.5 mg, 0.28 mmol) in DCM (1.9 mL) was stirred atroom temperature for 2 h. Then sodium triacetoxyborohydride (60 mg, 0.28mmol) and acetic acid (16.0 μl, 0.28 mmol) was added. The mixture wasfurther stirred at room temperature for 1 h. The reaction was quenchedby aq. NH₄OH solution and extracted with DCM. The organic phase wasdried over MgSO₄, and then filtered. The filtrate was concentrated andthe crude material was used directly for next step. LC-MS calculated forC₃₁H₃₁ClN₅O₃ (M+H)⁺: m/z=556.2; found 556.3.

Step 3:N-(3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide

This compound was prepared using similar procedures as described forExample 36, Step 6 withN-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamidereplacing tert-butyl2-((3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate.LC-MS calculated for C₃₁H₂₉ClN₅O₃ (M+H)⁺: m/z=554.2; found 554.3.

Step 4:3-(((7-chloro-2-(3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)(methyl)amino)propanoic Acid

This compound was prepared using similar procedures as described forExample 36, Step 7 with 3-(methylamino)propanoic acid replacing(S)-pyrrolidine-3-carboxylic acid. The reaction was diluted with MeOHand then purified by prep-HPLC (pH=10, acetonitrile/water+NH₄OH) to givethe desired product. LC-MS calculated for C₃₅H₃₈ClN₆O₄ (M+H)⁺:m/z=641.3; found 641.3.

Example 43(R)-1-((7-chloro-2-(2′-chloro-2-methyl-3′-(4-(methylamino)piperidin-1-yl)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: 8-(3-bromo-2-chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane

A mixture of 1,3-dibromo-2-chlorobenzene (2.20 g, 8.80 mmol),1,4-dioxa-8-azaspiro[4.5]decane (1.260 g, 8.80 mmol), palladium(II)acetate (0.20 g, 0.88 mmol),(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.55 g, 0.88 mmol), andcesium carbonate (7.17 g, 22.01 mmol) in 1,4-dioxane (30 mL) was placedin a vial and stirred at 90° C. for 12 hrs. The mixture was filteredthrough a pad of Celite and washed with EtOAc and the solvent wasremoved under reduced pressure to give a crude product, which waspurified by column chromatography (eluting with EtOAc/Hexanes 0%-100%).LC-MS calculated for C₁₃H₁₆BrClNO₂ (M+H)⁺: m/z=332.0; found 332.1.

Step 2:(7-chloro-2-(2′-chloro-2-methyl-3′-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)biphenyl-3-yl)benzo[d]oxazol-5-yl)methanol

A mixture of 8-(3-bromo-2-chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane(83 mg, 0.25 mmol),(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)benzo[d]oxazol-5-yl)methanol (Example 1, Step 5; 100 mg, 0.250mmol), sodium carbonate (53.0 mg, 0.500 mmol), andtetrakis(triphenylphosphine)palladium (29 mg, 0.025 mmol) in a mixedwater (500 μL) and 1,4-dioxane (4500 μL) was purged with N₂ and thenstirred at 100° C. for 3 hrs. The reaction was cooled to roomtemperature and then diluted with EtOAc and water. The aqueous phase wasextracted with EtOAc. The organic phase was dried over MgSO₄, filteredand the filtrate was concentrated under reduced pressure. The crudematerial was purified by flash chromatography on a silica gel (elutingwith EtOAc/Hexanes, 0-100%) to give the desired product. LC-MScalculated for C₂₈H₂₇Cl₂N₂O₄ (M+H)⁺: m/z=525.1; found 525.1.

Step 3:1-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)piperidin-4-one

To a solution of(7-chloro-2-(2′-chloro-2-methyl-3′-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)biphenyl-3-yl)benzo[d]oxazol-5-yl)methanol(320 mg, 0.67 mmol) in acetone (5 mL) was added 5 mL of 1N HCl at roomtemperature, the mixture was stirred at 45° C. for 3 hrs. Solid NaHCO₃was then added to quench the reaction. The mixture was extracted withEtOAc for three times. The organic phases were combined, dried overMgSO₄, filtered and the filtrate was concentrated. The residue was useddirectly without further purification. LC-MS calculated forC₂₆H₂₃Cl₂N₂O₃ (M+H)⁺: m/z=481.1; found 481.1.

Step 4:(7-chloro-2-(2′-chloro-2-methyl-3′-(4-(methylamino)piperidin-1-yl)biphenyl-3-yl)benzo[d]oxazol-5-yl)methanol

A mixture of1-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)piperidin-4-one(31 mg, 0.06 mmol) and methylamine THF solution (60 μL, 0.13 mmol) inDCM (500 μL) was stirred at room temperature for 2 hrs. Then sodiumtriacetoxyborohydride (27 mg, 0.13 mmol) was added. The mixture wasfurther stirred at room temperature for 3 hrs. The reaction was dilutedwith MeOH and concentrated and purified by column chromatography(eluting with MeOH/DCM, 0-50%). LC-MS calculated for C₂₇H₂₈Cl₂N₃O₂(M+H)⁺: m/z=496.1; found 496.2.

Step 5:7-chloro-2-(2′-chloro-2-methyl-3′-(4-(methylamino)piperidin-1-yl)biphenyl-3-yl)benzo[d]oxazole-5-carbaldehyde

To(7-chloro-2-(2′-chloro-2-methyl-3′-(4-(methylamino)piperidin-1-yl)biphenyl-3-yl)benzo[d]oxazol-5-yl)methanol(20 mg, 0.05 mmol) in DCM (2 mL) was added MnO₂ (79 mg, 0.91 mmol) inone portion at rt, and the resulting mixture was stirred at 45° C. for20 min. The reaction was filtered and the filtrate was concentrated. Theresidue was used directly without further purification. LC-MS calculatedfor C₂₇H₂₆Cl₂N₃O₂ (M+H)⁺: m/z=494.1; found 494.2.

Step 6:(R)-1-((7-chloro-2-(2′-chloro-2-methyl-3′-(4-(methylamino)piperidin-1-yl)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of7-chloro-2-(2′-chloro-2-methyl-3′-(4-(methylamino)piperidin-1-yl)biphenyl-3-yl)benzo[d]oxazole-5-carbaldehyde(10.1 mg, 0.02 mmol), triethylamine (5.41 μl, 0.039 mmol) and(R)-pyrrolidine-3-carboxylic acid (4.47 mg, 0.039 mmol) in DCM (1129 μL)was stirred at room temperature for 2 hrs. Then sodiumtriacetoxyborohydride (8.23 mg, 0.039 mmol) and acetic acid (3.33 μl,0.058 mmol) was added. The mixture was further stirred at roomtemperature for 1 h. The reaction was diluted with MeOH and thenpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as TFA salt. LC-MS calculated for C₃₂H₃₅Cl₂N₄O₃ (M+H)⁺:m/z=593.2; found 593.3.

Example 44(R)-1-((7-chloro-2-(2′-chloro-3′-(4-(cyclopropylamino)piperidin-1-yl)-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 43 with cyclopropanamine replacing methylamine in Step 4. Thereaction mixture was diluted with MeOH and then purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as TFA salt.LC-MS calculated for C₃₄H₃₇Cl₂N₄O₃ (M+H)⁺: m/z=619.2; found 619.2.

Example 45(R)-1-((7-chloro-2-(2′-chloro-3′-(4-((1s,3s)-3-hydroxycyclobutylamino)piperidin-1-yl)-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 43 with cis-3-aminocyclobutanol replacing methylamine in Step 4.The reaction mixture was diluted with MeOH and then purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₃₅H₃₉Cl₂N₄O₄ (M+H)⁺: m/z=649.2; found649.2.

Example 46(R)-1-((7-chloro-2-(2′-chloro-3′-(4-((1-(hydroxymethyl)cyclobutyl)methylamino)piperidin-1-yl)-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 43 with (1-(aminomethyl)cyclobutyl)methanol replacingmethylamine in Step 4. The reaction mixture was diluted with MeOH andthen purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as TFA salt. LC-MS calculated for C₃₇H₄₃Cl₂N₄O₄ (M+H)⁺:m/z=677.2; found 677.2.

Example 47(R)-1-((2-(2′-chloro-3′-(4-((1s,3s)-3-hydroxycyclobutylamino)piperidin-1-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:2-(2′-chloro-2-methyl-3′-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)biphenyl-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrile

A mixture of(7-chloro-2-(2′-chloro-2-methyl-3′-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanol(Example 43, step 2: 94 mg, 0.179 mmol),[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (14.21 mg, 0.018 mmol), potassium hexacyanoferrate(II)trihydrate (113 mg, 0.268 mmol) and potassium acetate (8.78 mg, 0.089mmol) in 1,4-dioxane (2 ml)/water (2 ml) was stirred and heated at 100°C. for 1 h. After cooling to rt, the reaction was diluted with EtOAc andwater, extracted with EtOAc. The combined organic phase was dried overMgSO₄ and concentrated. The crude material was used directly in the nextstep. LC-MS calculated for C₂₉H₂₇ClN₃O₄ (M+H)⁺: m/z=516.2; found 516.2.

Step 2:(R)-1-((2-(2′-chloro-3′-(4-((1s,3s)-3-hydroxycyclobutylamino)piperidin-1-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 43 with2-(2′-chloro-2-methyl-3′-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)biphenyl-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrilereplacing(7-chloro-2-(2′-chloro-2-methyl-3′-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)biphenyl-3-yl)benzo[d]oxazol-5-yl)methanolin Step 3 and cis-3-aminocyclobutanol replacing methylamine in Step 4.The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₃₆H₃₉ClN₅O₄ (M+H)⁺: m/z=640.3; found 640.2.

Example 48(R)-1-((2-(2′-chloro-3′-(4-(ethyl(2-hydroxyethyl)amino)piperidin-1-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 47 with 2-(ethylamino)ethanol replacing cis-3-aminocyclobutanol.It was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as TFA salt. LC-MS calculated for C₃₆H₄₁ClN₅O₄ (M+H)⁺:m/z=642.3; found 642.2.

Example 49(R)-1-((2-(2′-chloro-3′-(4-(ethyl((1s,3s)-3-hydroxycyclobutyl)amino)piperidin-1-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution of(R)-1-((2-(2′-chloro-3′-(4-((1s,3s)-3-hydroxycyclobutylamino)piperidin-1-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (Example 47; 11 mg, 0.016 mmol) and acetaldehyde (3.44 mg, 0.078mmol) in DCM (500 μL) was stirred at room temperature for 2 hrs. Thensodium triacetoxyborohydride (6.62 mg, 0.031 mmol) was added. Themixture was further stirred at room temperature for 3 hrs. The reactionwas diluted with MeOH and then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₃₈H₄₃ClN₅O₄ (M+H)⁺: m/z=668.3; found 668.3.

Example 50(S)-1-((2-(2′-chloro-3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: tert-butyl2-(3-bromo-2-chlorophenylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

Potassium tert-butoxide in THF (1.0 M, 3.39 mL, 3.39 mmol) was added toa solution of 5-tert-butyl 2-methyl1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-2,5(4H)-dicarboxylate(Example 36, Step 2: 500 mg, 1.69 mmol) and 3-bromo-2-chloroaniline(350.0 mg, 1.69 mmol) in tetrahydrofuran (12.0 mL). After stirred atroom temperature for 1 h, the reaction mixture was quenched with water,and extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by flash chromatography on asilica gel column eluting with 50% ethyl acetate in hexanes to affordthe desired product. LCMS calculated for C₁₉H₂₃BrClN₄O₃ (M+H)⁺:m/z=469.1; found 469.1.

Step 2:N-(3-bromo-2-chlorophenyl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide

To a solution of tert-butyl2-((3-bromo-2-chlorophenyl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate(160 mg, 0.341 mmol) in DCM (3 mL) was added trifluoroacetic acid (0.5mL). The solution was stirred at r.t. for 1 h. then concentrate todryness. The residue was dissolved in DCM (2.0 mL) and ACN (1 mL) thenformaldehyde (37 wt % in water, 0.2 mL) was added. The resulting mixturewas stirred at r.t. for 10 min, then sodium triacetoxyborohydride (217mg, 1.022 mmol) was added. The reaction mixture was continued to stir atr.t. overnight. The reaction was quenched with sat. NH₄Cl solution,extracted with EtOAc. The combined organic phase was dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford the desiredproduct, which was used directly in the next step without furtherpurification. LC-MS calculated for C₁₅H₁₇BrClN₄O (M+H)⁺: m/z=383.0;found 383.0.

Step 3:N-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide

A mixture ofN-(3-bromo-2-chlorophenyl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide(150 mg, 0.391 mmol),(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol(Example 1, Step 5:188 mg, 0.469 mmol), anddichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II) (17.7mg, 0.023 mmol) in t-BuOH (5 ml) was added cesium carbonate (255 mg,0.782 mmol) and a few drops of water. The reaction mixture was purgedwith nitrogen and then stirred at 100° C. for 5 hrs. After being cooledto room temperature, the reaction mixture was extracted with ethylacetate. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by flash chromatography on a silica gel column eluting with0 to 10% methanol in DCM to afford the desired product. LC-MS calculatedfor C₃₀H₂₈Cl₂N₅O₃ (M+H)⁺: m/z=576.2; found 576.1.

Step 4:N-(2-chloro-3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide

A mixture ofN-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide(140 mg, 0.24 mmol),[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3, 19.3 mg, 0.024 mmol),potassium hexacyanoferrate(II) trihydrate (103 mg, 0.24 mmol) andpotassium acetate (4.8 mg, 0.049 mmol) in 1,4-dioxane (3.0 mL)/water(3.0 mL) was purged with nitrogen and then stirred at 100° C. for 1 h.After being cooled to room temperature, the reaction was extracted withethyl acetate. The combined organic phases was dried over Na₂SO₄ andconcentrated under reduced pressure. The crude was used directly in thenext step without further purification. LC-MS calculated forC₃₁H₂₈ClN₆O₃ (M+H)⁺: m/z=567.2; found 567.2.

Step 5:N-(2-chloro-3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide

To a stirred solution ofN-(2-chloro-3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide(140.0 mg, 0.247 mmol) in DCM (3.0 ml) was added sodium bicarbonate (207mg, 2.47 mmol) and dess-martin periodinane (157 mg, 0.370 mmol). Theresulted mixture was stirred at rt for 2 hrs, then filtered. Thefiltrate was concentrated under reduced pressure. The residue was usedin the next step directly without further purification. LC-MS calculatedfor C₃₁H₂₆ClN₆O₃ (M+H)⁺: m/z=565.2; found 565.1.

Step 6:(S)-1-((2-(2′-chloro-3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution ofN-(2-chloro-3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide(65 mg, 0.115 mmol) in DCM (1 ml) was added (S)-pyrrolidine-3-carboxylicacid (66.2 mg, 0.575 mmol) and DIEA (0.161 ml, 0.920 mmol). The mixturewas stirred at r.t. for 60 min, then sodium triacetoxyborohydride (73.1mg, 0.345 mmol) was added. The resulting mixture was stirred at r.t.overnight then concentrated. The residue was purified via prep-HPLC(pH=2, MeCN/water with TFA) to give the desired product as the TFA salt.LC-MS calculated for C₃₆H₃₅ClN₇O₄ (M+H)⁺: m/z=664.2; found 664.2.

Example 51(S)-1-((7-cyano-2-(3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2′-fluoro-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedure as described forExample 50 with 3-bromo-2-fluoro aniline replacing3-bromo-2-chloroaniline in Step 1. It was purified via pH 2 preparativeHPLC (MeCN/water with TFA) to give the desired product as its TFA salt.LC-MS calculated for C₃₆H₃₅FN₇O₄ (M+H)⁺: m/z=648.2; found 648.3.

Example 52(S)-1-((2-(2′-chloro-3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicAcid

This compound was prepared using similar procedure as described forExample 50 with (S)-piperidine-2-carboxylic acid replacing(S)-pyrrolidine-3-carboxylic acid in Step 6. It was purified via pH 2preparative HPLC (MeCN/water with TFA) to give the desired product asits TFA salt. LC-MS calculated for C₃₇H₃₇ClN₇O₄ (M+H)⁺: m/z=678.3; found678.2.

Example 53(R)-1-((2-(2′-chloro-3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedure as described forExample 50 with (R)-pyrrolidine-3-carboxylic acid replacing(S)-pyrrolidine-3-carboxylic acid in Step 6. It was purified via pH 2preparative HPLC (MeCN/water with TFA) to give the desired product asits TFA salt. LC-MS calculated for C₃₆H₃₅ClN₇O₄ (M+H)⁺: m/z=664.2; found664.2.

Example 54(S)-1-((2-(2′-chloro-2-methyl-3′-(5-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: tert-butyl2-(3-bromo-2-chlorophenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

A mixture of tert-butyl1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (150 mg,0.672 mmol; Astatech, cat #SC2911), potassium phosphate tribasic (428mg, 2.015 mmol), 1,3-dibromo-2-chlorobenzene (363 mg, 1.344 mmol), andcopper(I) iodide (12.79 mg, 0.067 mmol) was degassed and backfilled withN₂ three times. To the mixture was addedtrans-N,N′-dimethylcyclohexane-1,2-diamine (42.4 μl, 0.134 mmol) andtoluene (2.2 mL). Then the mixture was allowed to stir at 110° C.overnight. The mixture was cooled to room temperature, filtered andconcentrated. The residue was purified on silica gel column eluting with0-80% EtOAc in Hexanes to give desired product. LC-MS calculated forC₁₇H₂₀BrClN₃O₂ (M+H)⁺: m/z=414.0; found 414.0.

Step 2:5-(hydroxymethyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile

A mixture of(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol(Example 1, Step 5: 40 mg, 0.100 mmol),[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (15.89 mg, 0.020 mmol), potassium hexacyanoferrate(II)trihydrate (42.3 mg, 0.100 mmol) and potassium acetate (3.93 mg, 0.040mmol) in 1,4-dioxane (0.5 mL) and water (0.5 mL) was purged with N₂ andheated at 100° C. for 1 h. After cooling to room temperature, thereaction mixture was used directly in next step without furtherpurification. LC-MS calculated for C₂₂H₂₄BN₂O₄ (M+H)⁺: m/z=391.2; found:391.2.

Step 3: tert-butyl2-(2-chloro-3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

(1,1′-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (7.32 mg,10.00 μmol) was added to a mixture of5-(hydroxymethyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile(0.039 g, 0.100 mmol), tert-butyl2-(3-bromo-2-chlorophenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(0.041 g, 0.10 mmol) and sodium carbonate (0.021 g, 0.200 mmol) in1,4-dioxane (0.278 ml) and water (0.056 ml). The mixture was purged withN₂ and heated at 90° C. for 2 h. The mixture was concentrated anddiluted with EtOAc and washed with water. The organic layer was driedover Na₂SO₄ and concentrated under reduce pressure. The residue was usedin next step without further purification. LC-MS calculated forC₃₃H₃₁ClN₅O₄ (M+H)⁺: m/z=596.2; found 596.3.

Step 4: tert-butyl2-(2-chloro-3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

Dess-Martin periodinane (0.064 g, 0.150 mmol) was added to a DCM (0.33mL) solution of tert-butyl2-(2-chloro-3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(0.060 g, 0.1 mmol) and sodium bicarbonate (0.025 g, 0.300 mmol) at roomtemperature. After 1 h, the mixture was concentrated and purified bysilica gel column eluting with 0 to 80% EtOAc in hexanes. LC-MScalculated for C₃₃H₂₉ClN₅O₄ (M+H)⁺: m/z=594.2; found 594.2.

Step 5:(S)-1-((2-(3′-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-2′-chloro-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of tert-butyl2-(2-chloro-3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(15 mg, 0.025 mmol) and (S)-pyrrolidine-3-carboxylic acid (5.81 mg,0.050 mmol), hunig's base (8.82 μl, 0.050 mmol) in DCM (252 μl) wasallowed to stir at room temperature for 2 h. Then sodiumtriacetoxyborohydride (8.03 mg, 0.038 mmol) was added to the mixture.The resulting mixture was stirred at room temperature for 1 h then itwas diluted with DCM and washed with water and back extracted withDCM/iPrOH. The organic layers were combined and dried over sodiumsulfate and concentrated and the residue was used in next step withoutfurther purification. LC-MS calculated for C₃₈H₃₈ClN₆O₅ (M+H)⁺:m/z=693.3; found 693.3.

Step 6:(S)-1-((2-(2′-chloro-2-methyl-3′-(4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

TFA (0.5 mL) was added to a DCM (1 mL) solution of(S)-1-((2-(3′-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-2′-chloro-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (14 mg, 0.025 mmol) at room temperature. After 1 h, the mixture wasconcentrated and used in next step without further purification. LC-MScalculated for C₃₃H₃₀ClN₆O₃ (M+H)⁺: m/z=593.2; found 593.1.

Step 7:(S)-1-((2-(2′-chloro-2-methyl-3′-(5-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of(S)-1-((2-(2′-chloro-2-methyl-3′-(4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (10 mg, 0.017 mmol) and formaldehyde 37% w/w in water (1.013 mg,0.034 mmol) in DCM (169 μl) was allowed to stir for 2 h. Then sodiumtriacetoxyborohydride (7.0 mg, 0.034 mmol) was added to the mixture.After 2 h, the mixture was concentrated and diluted with MeOH and thenpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as TFA salt. LC-MS calculated for C₃₄H₃₂ClN₆O₃ (M+H)⁺:m/z=607.2; found 607.3.

Example 55(R)-1-((2-(2′-chloro-2-methyl-3′-(5-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:(R)-1-((2-(2′-chloro-3′-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar method in Example 54, Step 1-6with tert-butyl 4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate(Astatech, cat #35882) replacing tert-butyl1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate in Step 1and with (R)-pyrrolidine-3-carboxylic acid replacing(S)-pyrrolidine-3-carboxylic acid in Step 5. LC-MS calculated forC₃₂H₂₈ClN₆O₃ (M+H)⁺: m/z=579.2; found 579.1.

Step 2:(R)-1-((2-(2′-chloro-2-methyl-3′-(5-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar method in Example 54, Step 7with(R)-1-((2-(2′-chloro-3′-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid replacing(S)-1-((2-(2′-chloro-2-methyl-3′-(4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid. It was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) togive the desired product as TFA salt. LC-MS calculated for C₃₃H₃₀ClN₆O₃(M+H)⁺: m/z=593.2; found 593.2.

Example 56(R)-1-((2-(2′-chloro-3′-(5-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar method in Example 55 withacetone replacing formaldehyde in Step 2. It was purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as TFA salt.LC-MS calculated for C₃₅H₃₄ClN₆O₃ (M+H)⁺: m/z=621.2; found 621.2.

Example 57(R)-1-((2-(2′-chloro-2-methyl-3′-(6-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar method in Example 54 withtert-butyl 1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate(Astatech, cat #79248) replacing tert-butyl1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate in Step 1.It was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as TFA salt. LC-MS calculated for C₃₄H₃₂ClN₆O₃ (M+H)⁺:m/z=607.3; found 607.3.

Example 58(R)-1-((2-(2′-chloro-3′-(6-ethyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar method in Example 57 withacetaldehyde replacing formaldehyde. It was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₃₅H₃₄ClN₆O₃ (M+H)⁺: m/z=621.2; found 621.2.

Example 59(R)-1-((7-chloro-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:(2-(3′-bromo-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-chlorobenzo[d]oxazol-5-yl)methanol

To a solution of(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol(Example 1, Step 5: 11.3 g, 28.4 mmol) and 1,3-dibromo-2-methylbenzene(14.17 g, 56.7 mmol) in H₂O (30 mL) and 1,4-dioxane (120 ml) was addedNa₂CO₃ (6.01 g, 56.7 mmol) and PdCl₂(dppf)-CH₂Cl₂ adduct (2.316 g, 2.84mmol). The resulted mixture was stirred in a closed vial flushed withnitrogen at 100° C. for 1.5 h. The reaction mixture was concentrated,followed by extraction with dichloromethane (25 mL×3). The combinedorganic layers were dried Na₂SO₄, filtered and concentrated. The crudeproduct was added to a silica gel column and was eluted with ethylacetate/dichloromethane from 0% to 40% to give(2-(3′-bromo-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-chlorobenzo[d]oxazol-5-yl)methanol(10.2 g, 23.0 mmol, 81% yield). LC-MS calculated for C₂₂H₁₈BrClNO₂(M+H)⁺: m/z=442.0; found 442.1.

Step 2:(7-chloro-2-(2,2′-dimethyl-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanol

(2-(3′-bromo-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-chlorobenzo[d]oxazol-5-yl)methanol(6.52 g, 14.7 mmol) was dissolved in dioxane (14.7 mL) to give a paleyellow solution. B₂Pin₂ (4.49 g, 17.7 mmol), potassium acetate (2.89 g,29.5 mmol) and PdCl₂(dppf)-CH₂Cl₂ adduct (1.20 g, 1.47 mmol) were addedto the reaction mixture. The reaction mixture was heated to 100° C.After 12 h, saturated NaHCO₃ (25 mL) was added to the reaction mixturefollowed by extraction with dichloromethane (25 mL×3). The combinedorganic layers were dried Na₂SO₄, filtered and concentrated. The crudeproduct was added to a silica gel column and was eluted with ethylacetate/hexane from 0% to 60% to give(7-chloro-2-(2,2′-dimethyl-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanol(6.33 g, 12.9 mmol, 88% yield) as a yellow foam. LC-MS calculated forC₂₈H₃₀BClNO₄ (M+H)⁺: m/z=490.2; found 490.1.

Step 3: tert-butyl2-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

(7-chloro-2-(2,2′-dimethyl-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanol(2.98 g, 6.08 mmol), tert-butyl2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (AstaTech,cat #AB1021: 2.33 g, 7.29 mmol), Na₂CO₃ (1.29 g, 12.2 mmol) andPdCl₂(dppf)-CH₂Cl₂ adduct (496 mg, 0.608 mmol) in 1,4-dioxane (60 ml)and water (15 mL) were stirred in a closed vial flushed with nitrogen at100° C. for 1 h. Saturated NaHCO₃ (50 mL) was added to the reactionmixture followed by extraction with dichloromethane (25 mL×4). Thecombined organic layers were dried Na₂SO₄, filtered and concentrated.The crude product was added to a silica gel column and was eluted withethyl acetate/hexane from 0% to 60% to give tert-butyl2-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(1.80 g, 2.99 mmol, 49.2% yield) as a yellow oil. LC-MS calculated forC₃₃H₃₃ClN₃O₄S (M+H)⁺: m/z=602.2; found 602.1.

Step 4: tert-butyl2-(3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl2-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(222 mg, 0.368 mmol) in DCM (3 mL) was added Dess-Martin periodinane(234 mg, 0.552 mmol). After 1 h, saturated NaHCO₃ (5 mL) was added tothe reaction mixture followed by extraction with dichloromethane (5mL×3). The combined organic layers were dried Na₂SO₄, filtered andconcentrated. The crude product was added to a silica gel column and waseluted with ethyl acetate/hexane from 0% to 30% to give tert-butyl2-(3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(143 mg, 0.238 mmol, 64.7% yield). LC-MS calculated for C₃₃H₃₁ClN₃O₄S(M+H)⁺: m/z=600.2; found 600.1.

Step 5:(R)-1-((2-(3′-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-chlorobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution of tert-butyl2-(3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(70 mg, 0.117 mmol) in DMF (1.2 mL) was added(R)-pyrrolidine-3-carboxylic acid (40.2 mg, 0.350 mmol). After 1 h,sodium cyanoborohydride (15 mg, 0.233 mmol) was added to the reactionmixture. After 2 h, saturated NaHCO₃ (5 mL) was added followed byextraction with dichloromethane (5 mL×4). The combined organic layerswere dried Na₂SO₄, filtered and concentrated. The crude product was useddirectly in the next step. LC-MS calculated for C₃₈H₄₀ClN₄O₅S (M+H)⁺:m/z=699.2; found 699.3.

Step 6:(R)-1-((7-chloro-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution of(R)-1-((2-(3′-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-chlorobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (82 mg, 0.117 mmol) in DCM (1 mL) was added TFA (0.5 mL). After 2h, the reaction mixture was concentrated, and then the crude product wasused directly in the next step. LC-MS calculated for C₃₃H₃₂ClN₄O₃S(M+H)⁺: m/z=599.2; found 599.3.

Step 7:(R)-1-((7-chloro-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

In a 1 dram vial(R)-1-((7-chloro-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (50 mg, 0.083 mmol) was dissolved in DCM (417 μl) to give a yellowsolution. Acetone (30.6 μl, 0.417 mmol) and DIPEA (29.2 μl, 0.167 mmol)were added to the reaction mixture. After 1 h, sodiumtriacetoxyborohydride (88 mg, 0.417 mmol) was added to the reactionmixture. After 5 h, the reaction mixture was concentrated. The reactionmixture was diluted with MeOH then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₃₆H₃₈ClN₄O₃S (M+H)⁺: m/z=641.2; found 641.3. ¹HNMR (500 MHz, DMSO-d6) δ 8.16 (dd, J=7.9, 1.2 Hz, 1H), 8.02 (d, J=1.1Hz, 1H), 7.78 (d, J=1.2 Hz, 1H), 7.67 (dd, J=7.8, 1.1 Hz, 1H), 7.56 (t,J=7.7 Hz, 1H), 7.46 (m, 2H), 7.32 (d, J=6.5 Hz, 1H), 4.77-4.68 (m, 2H),4.54 (s, 2H), 3.85-3.12 (m, 10H), 2.43 (s, 3H), 2.18 (s, 3H), 2.05 (s,2H), 1.36 (s, 3H), 1.35 (s, 3H).

Example 60(R)-1-((7-chloro-2-(3′-(5-ethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 59 with acetaldehyde replacing acetone in Step 7. The reactionmixture was diluted with MeOH then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₃₅H₃₆ClN₄O₃S (M+H)⁺: m/z=627.2; found 627.3.

Example 61(R)-1-((7-chloro-2-(3′-(5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:(R)-1-((2-(3′-(5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-chlorobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 59 with (tert-Butyldimethylsilyloxy)acetaldehyde (Aldrich, cat#449458) replacing acetone in Step 7. The reaction mixture wasconcentrated, and then the crude product was used directly in the nextstep. LC-MS calculated for C₄₁H₅₀ClN₄O₄SSi (M+H)⁺: m/z=757.2; found757.3.

Step 2:(R)-1-((7-chloro-2-(3′-(5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

(R)-1-((2-(3′-(5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-chlorobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (20 mg, 0.031 mmol) was dissolved in THF (1 mL), then treated with1N HCl (0.1 mL). After 2 h, the reaction mixture was diluted with MeOHthen purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₃₅H₃₆ClN₄O₄S(M+H)⁺: m/z=643.2; found 643.2. ¹H NMR (500 MHz, DMSO-d₆) δ 10.37 (br,1H), 8.16 (d, J=6.7 Hz, 1H), 8.02 (d, J=1.1 Hz, 1H), 7.78 (d, J=1.2 Hz,1H), 7.69 (d, J=6.7 Hz, 1H), 7.56 (t, J=7.7 Hz, 1H), 7.48-7.42 (m, 2H),7.32 (d, J=6.6 Hz, 1H), 4.88-4.33 (m, 2H), 4.53 (s, 2H), 3.83 (t, J=5.2Hz, 2H), 3.68-2.99 (m, 13H), 2.42 (s, 3H), 2.19 (s, 3H).

Example 62(3R)-1-((7-chloro-2-(3′-(5-(1-hydroxypropan-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:(3R)-1-((2-(3′-(5-(1-acetoxypropan-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-chlorobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 59 with acetoxyacetone (Alfa Aesar, cat #H31346) replacingacetone in Step 7. The reaction mixture was concentrated, and then thecrude product was used directly in the next step. LC-MS calculated forC₃₈H₄₀ClN₄O₅S (M+H)⁺: m/z=699.2; found 699.3.

Step 2:(3R)-1-((7-chloro-2-(3′-(5-(1-hydroxypropan-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

(3R)-1-((2-(3′-(5-(1-acetoxypropan-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-chlorobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (20 mg, 0.031 mmol) was dissolved in dioxane (1 mL), then treatedwith 1N NaOH (0.1 mL). After 2 h, the reaction mixture was diluted withMeOH then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to givethe desired product as the TFA salt. LC-MS calculated for C₃₆H₃₈ClN₄O₄S(M+H)⁺: m/z=657.2; found 657.2.

Example 63(R)-1-((7-cyano-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: tert-butyl2-(3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

In a 4 dram vial tert-butyl2-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(Example 59, Step 3; 900 mg, 1.50 mmol) and potassium ferrocyanide(II)hydrate (947 mg, 2.24 mmol) were dissolved in 1,4-dioxane (10 ml) andwater (4.5 ml). Potassium acetate (367 mg, 3.74 mmol) and[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (119 mg, 0.15 mmol) were added to thereaction mixture. The reaction mixture was heated to 100° C. After 2 h,saturated NaHCO₃ (15 mL) was added to the reaction mixture followed byextraction with dichloromethane (10 mL×4). The combined organic layerswere dried Na₂SO₄, filtered and concentrated. The crude product wasadded to a silica gel column and was eluted with ethyl acetate/hexanefrom 10% to 60% to give tert-butyl2-(3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(702 mg, 1.18 mmol, 79% yield) as a yellow oil. LC-MS calculated forC₃₄H₃₃N₄O₄S (M+H)⁺: m/z=593.2; found 593.1.

Step 2: tert-butyl2-(3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl2-(3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(150 mg, 0.253 mmol) in DCM (2 mL) was added Dess-Martin periodinane(161 mg, 0.380 mmol). After 1 h, saturated NaHCO₃ (5 mL) was added tothe reaction mixture followed by extraction with dichloromethane (5mL×3). The combined organic layers were dried Na₂SO₄, filtered andconcentrated. The crude product was used for next step without furtherpurification. LC-MS calculated for C₃₄H₃₁N₄O₄S (M+H)⁺: m/z=591.2; found591.3.

Step 3:(R)-1-((2-(3′-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution of tert-butyl2-(3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(150 mg, 0.253 mmol) and DIPEA (20 uL) in DCM (3 mL) was added(R)-pyrrolidine-3-carboxylic acid (116 mg, 1.01 mmol). After 1 h, sodiumtriacetoxyborohydride (268 mg, 1.26 mmol) was added to the reactionmixture. After 2 h, saturated NaHCO₃ (5 mL) was added followed byextraction with dichloromethane (5 mL×4). The combined organic layerswere dried Na₂SO₄, filtered and concentrated. The crude product was useddirectly in the next step. LC-MS calculated for C₃₉H₄₀N₅O₅S (M+H)⁺:m/z=690.2; found 690.3.

Step 4:(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution of(R)-1-((2-(3′-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (175 mg, 0.253 mmol) was dissolved in DCM (2 mL) was added TFA (0.5mL). After 2 h, the reaction mixture was concentrated, and then thecrude product was used directly in the next step. LC-MS calculated forC₃₄H₃₂N₅O₃S (M+H)⁺: m/z=590.2; found 590.3.

Step 5:(R)-1-((7-cyano-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

In a 1 dram vial(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (50 mg, 0.083 mmol) was dissolved in DCM (500 μl) to give a yellowsolution. Acetone (30.6 μl, 0.417 mmol) and DIPEA (29.2 μl, 0.167 mmol)were added to the reaction mixture. After 1 h, sodiumtriacetoxyborohydride (88 mg, 0.417 mmol) was added to the reactionmixture. After 5 h, the reaction mixture was concentrated. The reactionmixture was diluted with MeOH then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₃₇H₃₈N₅O₃S (M+H)⁺: m/z=632.2; found 632.3. ¹H NMR(500 MHz, DMSO-d₆) δ 10.42 (br, 1H), 8.38 (d, J=1.3 Hz, 1H), 8.20 (dd,J=7.9, 1.2 Hz, 1H), 8.13 (d, J=1.4 Hz, 1H), 7.70-7.65 (m, 1H), 7.58 (t,J=7.7 Hz, 1H), 7.49-7.43 (m, 2H), 7.35-7.29 (m, 1H), 4.78-4.47 (m, 2H),4.57 (s, 2H), 3.86-3.08 (m, 10H), 2.44 (s, 3H), 2.29-2.00 (m, 2H), 2.18(s, 3H), 1.36 (s, 3H), 1.35 (s, 3H).

Example 64(R)-1-((7-cyano-2-(3′-(5-(cyclopropylmethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 63 with cyclopropanecarbaldehyde replacing acetone in Step 5.The reaction mixture was diluted with MeOH then purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₃₈H₃₈N₅O₃S (M+H)⁺: m/z=644.2; found 644.3.

Example 65(R)-1-((7-cyano-2-(3′-(5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:(R)-1-((2-(3′-(5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 63 with (tert-butyldimethylsilyloxy)acetaldehyde (Aldrich, cat#449458) replacing acetone in Step 5. The reaction mixture wasconcentrated, and then the crude product was used directly in the nextstep. LC-MS calculated for C₄₂H₅₀N₅O₄SSi (M+H)⁺: m/z=748.2; found 748.3.

Step 2:(R)-1-((7-cyano-2-(3′-(5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

(R)-1-((2-(3′-(5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (20 mg, 0.031 mmol) was dissolved in THF (1 mL), then treated with1N HCl (0.1 mL). After 2 h, the reaction mixture was diluted with MeOHthen purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₃₆H₃₆N₅O₄S(M+H)⁺: m/z=634.2; found 634.2. ¹H NMR (500 MHz, DMSO-d₆) δ 10.41 (br,1H), 8.39 (d, J=1.3 Hz, 1H), 8.21-8.18 (m, 1H), 8.12 (d, J=1.4 Hz, 1H),7.72-7.67 (m, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.51-7.42 (m, 2H), 7.32 (d,J=6.6 Hz, 1H), 4.86-4.45 (m, 2H), 4.57 (s, 2H), 3.83 (t, J=5.2 Hz, 2H),3.71-3.07 (m, 11H), 2.43 (s, 3H), 2.40-2.00 (m, 5H).

Example 66(3R)-1-((7-cyano-2-(3′-(5-(1-hydroxypropan-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:(3R)-1-((2-(3′-(5-(1-acetoxypropan-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 63 with acetoxyacetone (Alfa Aesar, cat #H31346) replacingacetone in Step 5. The reaction mixture was concentrated, and then thecrude product was used directly in the next step. LC-MS calculated forC₃₉H₄₀N₅O₅S (M+H)⁺: m/z=690.2; found 690.3.

Step 2:(3R)-1-((7-cyano-2-(3′-(5-(1-hydroxypropan-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

(3R)-1-((2-(3′-(5-(1-acetoxypropan-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (20 mg, 0.031 mmol) was dissolved in dioxane (1 mL), then treatedwith 1N NaOH (0.1 mL). After 2 h, the reaction mixture was diluted withMeOH then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to givethe desired product as the TFA salt. LC-MS calculated for C₃₇H₃₈N₅O₄S(M+H)⁺: m/z=648.2; found 648.2.

Example 67(S)-1-((7-cyano-2-(3′-(5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:(S)-1-((2-(3′-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution of tert-butyl2-(3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(Example 63, Step 2; 150 mg, 0.253 mmol) and DIPEA (20 uL) in DCM (3 mL)was added (S)-pyrrolidine-3-carboxylic acid (116 mg, 1.01 mmol). After 1h, sodium triacetoxyborohydride (268 mg, 1.26 mmol) was added to thereaction mixture. After 2 h, saturated NaHCO₃ (5 mL) was added followedby extraction with dichloromethane (5 mL×4). The combined organic layerswere dried Na₂SO₄, filtered and concentrated. The crude product was useddirectly in the next step. LC-MS calculated for C₃₉H₄₀N₅O₅S (M+H)⁺:m/z=690.2; found 690.3.

Step 2:(S)-1-((7-cyano-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution of(S)-1-((2-(3′-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (175 mg, 0.253 mmol) was dissolved in DCM (2 mL) was added TFA (0.5mL). After 2 h, the reaction mixture was concentrated, and then thecrude product was used directly in the next step. LC-MS calculated forC₃₄H₃₂N₅O₃S (M+H)⁺: m/z=590.2; found 590.3.

Step 3:(S)-1-((2-(3′-(5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

In a 1 dram vial(S)-1-((7-cyano-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (50 mg, 0.083 mmol) was dissolved in DCM (417 μl) to give a yellowsolution. (tert-Butyldimethylsilyloxy)acetaldehyde (Aldrich, cat#449458: 30.6 μl, 0.417 mmol) and DIPEA (29.2 μl, 0.167 mmol) were addedto the reaction mixture. After 1 h, sodium triacetoxyborohydride (88 mg,0.417 mmol) was added to the reaction mixture. After 5 h, the reactionmixture was concentrated, and then the crude product was used directlyin the next step. LC-MS calculated for C₄₂H₅₀N₅O₄SSi (M+H)⁺: m/z=748.3;found 748.3.

Step 4:(S)-1-((7-cyano-2-(3′-(5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

(S)-1-((2-(3′-(5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (20 mg, 0.031 mmol) was dissolved in THF (1 mL), then treated with1N HCl (0.1 mL). After 2 h, the reaction mixture was diluted with MeOHthen purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₃₆H₃₆N₅O₄S(M+H)⁺: m/z=634.2; found 634.2.

Example 681-((7-cyano-2-(3′-(5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicAcid

Step 1:1-((2-(3′-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicAcid

To a solution of tert-butyl2-(3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(Example 63, Step 2; 150 mg, 0.253 mmol) and DIPEA (20 uL) in DCM (3 mL)was added azetidine-3-carboxylic acid (116 mg, 1.01 mmol). After 1 h,sodium triacetoxyborohydride (268 mg, 1.26 mmol) was added to thereaction mixture. After 2 h, saturated NaHCO₃ (5 mL) was added followedby extraction with dichloromethane (5 mL×4). The combined organic layerswere dried Na₂SO₄, filtered and concentrated. The crude product was useddirectly in the next step. LC-MS calculated for C₃₈H₃₈N₅O₅S (M+H)⁺:m/z=676.2; found 676.3.

Step 2:1-((7-cyano-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicAcid

To a solution of1-((2-(3′-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicacid (175 mg, 0.253 mmol) was dissolved in DCM (2 mL) was added TFA (0.5mL). After 2 h, the reaction mixture was concentrated, and then thecrude product was used directly in the next step. LC-MS calculated forC₃₃H₃₀N₅O₃S (M+H)⁺: m/z=576.2; found 576.3.

Step 3:1-((2-(3′-(5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicAcid

In a 1 dram vial1-((7-cyano-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicacid (50 mg, 0.083 mmol) was dissolved in DCM (417 μl) to give a yellowsolution. (tert-Butyldimethylsilyloxy)acetaldehyde (Aldrich, cat#449458: 30.6 μl, 0.417 mmol) and DIPEA (29.2 μl, 0.167 mmol) were addedto the reaction mixture. After 1 h, sodium triacetoxyborohydride (88 mg,0.417 mmol) was added to the reaction mixture. After 5 h, the reactionmixture was concentrated, and then the crude product was used directlyin the next step. LC-MS calculated for C₄₁H₄₈N₅O₄SSi (M+H)⁺: m/z=734.2;found 734.3.

Step 4:1-((7-cyano-2-(3′-(5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicAcid

1-((2-(3′-(5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicacid (20 mg, 0.031 mmol) was dissolved in THF (1 mL), then treated with1N HCl (0.1 mL). After 2 h, the reaction mixture was diluted with MeOHthen purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₃₅H₃₄N₅O₄S(M+H)⁺: m/z=620.2; found 620.2.

Example 69(R)-1-((2-(2-chloro-2′-methyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: 3-bromo-2-chlorobenzaldehyde

To a solution of (3-bromo-2-chlorophenyl)methanol (AstaTech, cat#CL8936: 2.20 g, 10 mmol) in DCM (50 mL) was added Dess-Martinperiodinane (5.02 g, 12 mmol). After 1 h, saturated NaHCO₃ (50 mL) wasadded to the reaction mixture followed by extraction withdichloromethane (25 mL×3). The combined organic layers were driedNa₂SO₄, filtered and concentrated. The crude product was added to asilica gel column and was eluted with 0 to 30% EtOAc/Hexanes to give thedesired product (1.76 g, 80%). LC-MS calculated for C₇H₅BrClO (M+H)⁺:m/z=220.9; found 221.0.

Step 2: methyl2-(3-bromo-2-chlorophenyl)-7-chlorobenzo[d]oxazole-5-carboxylate

A mixture of methyl 3-amino-5-chloro-4-hydroxybenzoate (Example 1, Step2; 1.04 g, 5.16 mmol), 3-bromo-2-chlorobenzaldehyde (0.98 g, 4.92 mmol)in EtOH (25 ml) was placed in a vial and stirred at room temperature for1 h. The mixture was then concentrated. The residue was redissolved inmethylene chloride (25 mL) and dichlorodicyanoquinone (1.12 g, 4.92mmol) was added. The mixture was stirred at room temperature for 30 min.The reaction was diluted with methylene chloride and washed with anaqueous Na₂S₂O₃ solution and NaHCO₃ solution. The organic phase wasdried over MgSO₄, filtered and the filtrate was concentrated. The cruderesidue was used directly without further purification. LC-MS calculatedfor C₁₅H₉BrCl₂NO₃ (M+H)⁺: m/z=401.9; found 401.9.

Step 3: (2-(3-bromo-2-chlorophenyl)-7-chlorobenzo[d]oxazol-5-yl)methanol

To a solution of methyl2-(3-bromo-2-chlorophenyl)-7-chlorobenzo[d]oxazole-5-carboxylate (0.030g, 0.075 mmol) in THF (0.5 mL) was added DIBAL-H (0.187 ml, 0.187 mmol)at 0° C. After 1 h, saturated Rochelle's salt (2 mL) was added to thereaction mixture followed by extraction with ethyl acetate (5 mL×3). Thecombined organic layers were dried Na₂SO₄, filtered and concentrated.The organic layers were combined, dried over Na₂SO₄, concentrated, andpurified by flash chromatography on a silica gel column eluting with 0to 60% EtOAc/hexanes to give the desired product as a yellow solid.LC-MS calculated for C₁₄H₉BrCl₂NO₂ (M+H)⁺: m/z=373.9; found 374.0.

Step 4: tert-butyl2-(3-chloro-2-methylphenyl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate

To a solution of (3-chloro-2-methylphenyl)boronic acid (Combi-blocks,cat #BB-2035: 64 mg, 0.38 mmol), tert-butyl2-bromo-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate(AstaTech, cat #AB1021: 100 mg, 0.31 mmol) and sodium carbonate (100 mg,0.94 mmol) in tert-butyl alcohol (3.2 mL) and water (2 mL) was addedPd-127 (47 mg, 0.063 mmol). The resulting mixture was purged with N₂,then heated at 105° C. for 2 h. The reaction mixture was diluted withmethylene chloride, washed with sat'd NaHCO₃, water and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography on a silica gel columneluting with 0 to 40% ethyl acetate in hexanes to give the desiredproduct (114 mg, 83%). LC-MS calculated for C₁₈H₂₂ClN₂O₂S (M+H)⁺:m/z=365.1; found 365.2.

Step 5: tert-butyl2-[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate

A mixture of tert-butyl2-(3-chloro-2-methylphenyl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate(95 mg, 0.26 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (200 mg,0.78 mmol), palladium acetate (2.5 mg, 0.014 mmol), K₃PO₄ (170 mg, 0.78mmol) and 2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (11mg, 0.026 mmol) in 1,4-dioxane (1 mL) was degassed and stirred at r.t.for 3 d. The reaction mixture was diluted with methylene chloride,washed with sat'd NaHCO₃, water and brine. The organic layer was driedover Na₂SO₄, filtered and concentrated. The residue was purified byflash chromatography on a silica gel column eluting with 0 to 5% ethylacetate in methylene chloride to give the desired product (108 mg, 90%).LC-MS calculated for C₂₄H₃₄BN₂O₄S (M+H)⁺: m/z=457.2; found 457.2.

Step 6: tert-butyl2-(2′-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

In a nitrogen flushed 4 dram vial tert-butyl2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(28 mg, 0.037 mmol) and(2-(3-bromo-2-chlorophenyl)-7-chlorobenzo[d]oxazol-5-yl)methanol (14 mg,0.037 mmol) were dissolved in tBuOH (500 μl) and water (200 μl) to givea yellow solution. Na₂CO₃ (10 mg, 0.092 mmol) and Pd-127 (3 mg, 3.69μmol) were added to the reaction mixture in one portion. The reactionmixture was heated to 90° C. After 1 h, the reaction mixture was cooledto r.t. Saturated NaHCO₃ (volume) was added to the reaction mixturefollowed by extraction with ethyl acetate (5 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated. The crudeproduct was used without further purification. LC-MS calculated forC₃₂H₃₀Cl₂N₃O₄S (M+H)⁺: m/z=622.1; found 622.1.

Step 7: tert-butyl2-(2′-chloro-3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl2-(2′-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(23 mg, 0.037 mmol) in DCM (3 mL) was added Dess-Martin periodinane (23mg, 0.055 mmol). After 1 h, saturated NaHCO₃ (5 mL) was added to thereaction mixture followed by extraction with dichloromethane (5 mL×3).The combined organic layers were dried Na₂SO₄, filtered andconcentrated. The crude product was added to a silica gel column and waseluted with ethyl acetate/hexane from 0% to 30% to give tert-butyl2-(3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(14 mg, 0.024 mmol, 64.7% yield). LC-MS calculated for C₃₂H₂₈Cl₂N₃O₄S(M+H)⁺: m/z=620.2; found 620.1.

Step 8:(R)-1-((7-chloro-2-(2-chloro-2′-methyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution of tert-butyl2-(2′-chloro-3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(70 mg, 0.117 mmol) in DMF (1.2 mL) was added(R)-pyrrolidine-3-carboxylic acid (40.2 mg, 0.350 mmol). After 1 h,sodium cyanoborohydride (15 mg, 0.233 mmol) was added to the reactionmixture. After 2 h, the reaction mixture was diluted with DCM (1 mL) andtreated with TFA (0.5 mL). After 2 h, the reaction mixture was dilutedwith MeOH then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) togive the desired product as the TFA salt. LC-MS calculated forC₃₂H₂₉Cl₂N₄O₃S (M+H)⁺: m/z=619.2; found 619.3.

Step 9:(R)-1-((2-(2-chloro-2′-methyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

In a 1 dram vial(R)-1-((7-chloro-2-(2-chloro-2′-methyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (5 mg, 8.07 μmol) and potassium ferrocyanide(II) hydrate (2.211 μl,9.68 μmol) were dissolved in 1,4-dioxane (500 μl) and water (200 μl).Potassium acetate (8 mg, 50 μmol) and tBuXPhos Pd G3 (1.2 mg, 1.6 μmol)were added to the reaction mixture. The reaction mixture was heated to100° C. After 2 h, the reaction mixture was diluted with MeOH thenpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₃₃H₂₉ClN₅O₃S (M+H)⁺:m/z=610.2; found 610.3.

Example 70(R)-1-((7-chloro-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: tert-butyl2-(3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

To a microwave vial was added tert-butyl2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(Example 69, Step 5: 50 mg, 0.110 mmol),2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazole-5-carbaldehyde(Example 10, Step 1; 38.4 mg, 0.110 mmol),(1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (8.02 mg,10.96 μmol), sodium carbonate (23.22 mg, 0.219 mmol, 1,4-dioxane (5.0ml) and water (1.0 ml). The mixture was purged with N₂ and heated at 90°C. for 2 h. The reaction mixture was cooled to room temperature and thendiluted with EtOAc and water. The aqueous phase was extracted withEtOAc. The organic phase was dried over MgSO₄, filtered and the filtratewas concentrated under reduced pressure. The crude material was purifiedby flash chromatography (eluting with EtOAc/Hexanes, 0-100%) to give thedesired product (43 mg, 65%). LC-MS calculated for C₃₃H₃₁ClN₃O₄S (M+H)⁺:m/z=600.2; found 600.2.

Step 2:(R)-1-((7-chloro-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a mixture of tert-butyl2-(3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-3a,6,7,7a-tetrahydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(22 mg, 0.037 mmol) (R)-pyrrolidine-3-carboxylic acid (4.2 mg, 0.037mmol) in DCM (1.0 ml) was added sodium triacetoxyborohydride (7.7 mg,0.037 mmol) at room temperature. After stirring at room temperatureovernight, the reaction mixture was diluted with MeOH and then purifiedby prep-HPLC (pH=2, acetonitrile/water+TFA). After removing solvent, theresidue was treated with 1:1 TFA/DCM (2 mL) for 1 h. The solvent wasremoved in vacuo. The residue was purified with prep LCMS (pH 2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₃₃H₃₂ClN₄O₃S (M+H)⁺: m/z=599.2; found 599.2. ¹H NMR (500MHz, DMSO) δ 8.14 (m, 1H), 7.73 (d, J=1.0 Hz, 1H), 7.65 (m, 1H),7.58-7.48 (m, 2H), 7.42 (t, J=7.6 Hz, 2H), 7.30-7.24 (m, 1H), 3.97 (s,2H), 3.72 (m, 2H), 3.04 (m, 2H), 2.95 (m, 1H), 2.79-2.62 (m, 4H),2.60-2.48 (m, 2H), 2.43 (s, 3H), 2.19 (s, 3H), 1.98 (m, 2H).

Example 71(R)-1-((7-chloro-2-(2,2′-dimethyl-3′-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a mixture of(R)-1-((7-chloro-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (Example 70; 20 mg, 0.033 mmol), paraformaldehyde (5.0 mg, 0.167mmol) in CH₂Cl₂ (1.0 ml) was added sodium triacetoxyborohydride (14.1mg, 0.067 mmol) and resultant mixture was stirred overnight. Afterremoving solvent in vacuo, the mixture was diluted with MeOH and thenpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as TFA salt. LC-MS calculated for C₃₄H₃₄ClN₄O₃S (M+H)⁺:m/z=613.2; found 613.2. ¹H NMR (500 MHz, DMSO) δ 8.18 (d, J=6.9 Hz, 1H),8.03 (s, 1H), 7.79 (s, 1H), 7.71 (d, J=6.7 Hz, 1H), 7.58 (m, 1H), 7.47(m, 2H), 7.33 (d, J=6.7 Hz, 1H), 4.52 (m, 4H), 3.64-3.20 (m, 8H), 3.17(m, 1H), 2.99 (s, 3H), 2.42 (s, 3H), 2.38-2.05 (m, 2H), 2.21 (s, 3H).

Example 72(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a mixture of tert-butyl2-(3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-3a,6,7,7a-tetrahydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(Example 63, Step 2: 55 mg, 0.093 mmol), (R)-pyrrolidine-3-carboxylicacid (16.0 mg, 0.139 mmol) in CH₂C₁₂ (1.0 ml) was added sodiumtriacetoxyborohydride (19.7 mg, 0.093 mmol). After stirring at roomtemperature overnight, the reaction mixture was diluted with MeOH andthen purified by prep-HPLC (pH=2, acetonitrile/water+TFA). Afterremoving solvent, the residue was treated with 1:1 TFA/DCM (2 mL) for 1h. The solvent was removed in vacuo. The residue was purified by prepLCMS (pH 2, acetonitrile/water+TFA) to give the desired product as TFAsalt. LC-MS calculated for C₃₄H₃₂N₅O₃S (M+H)⁺: m/z=590.2; found 590.2.¹H NMR (600 MHz, DMSO) δ 8.42-8.39 (m, 1H), 8.24-8.19 (m, 1H), 8.14 (d,J=1.4 Hz, 1H), 7.76-7.67 (m, 1H), 7.64-7.56 (m, 1H), 7.51-7.44 (m, 2H),7.33 (d, J=6.7 Hz, 1H), 4.64-4.53 (m, 4H), 3.66 (m, 2H), 3.55 (m, 2H),3.51-3.44 (m, 3H), 3.27-3.21 (m, 2H), 3.10 (m, 2H), 2.45 (s, 3H), 2.20(s, 3H).

Example 73(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a microwave vial was added(R)-1-((7-chloro-2-(2,2′-dimethyl-3′-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (Example 71; 19 mg, 0.031 mmol), potassium ferrocyanide(II) hydrate(8.49 μl, 0.037 mmol),[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (2.462 mg, 3.10 μmol), potassium acetate(3.04 mg, 0.031 mmol), 1,4-dioxane (155 μl) and water (155 μl) The vialwas capped and sparged with nitrogen. The reaction was heated to 100° C.for 3 hours. After cooling to room temperature, the reaction mixture wasdiluted with ethyl acetate and water, the aqueous phase was extractedwith EtOAc. The organic phase was dried over MgSO₄, filtered and thefiltrate was concentrated under reduced pressure. The crude material waspurified by prep LCMS (pH 2, acetonitrile/water+TFA) to give the desiredproduct as TFA salt. LC-MS calculated for C₃₅H₃₄N₅O₃S (M+H)⁺: m/z=604.2;found 604.2. ¹H NMR (600 MHz, DMSO) δ 8.40 (d, J=1.3 Hz, 1H), 8.21 (m,1H), 8.14 (d, J=1.4 Hz, 1H), 7.71 (m, 1H), 7.60 (m, 1H), 7.51-7.45 (m,2H), 7.34 (m, 1H), 4.81-4.50 (m, 4H), 3.79-3.21 (m, 7H), 3.18 (m, 2H),3.01 (s, 3H), 2.45 (s, 3H), 2.33-2.09 (m, 2H), 2.21 (s, 3H).

Example 74(R)-1-((7-chloro-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: Benzyl(3R,4R)-3-(3-bromo-2-methylbenzamido)-4-hydroxypiperidine-1-carboxylate

A solution of 3-bromo-2-methylbenzoic acid (1.30 g, 6.05 mmol) andbenzyl (3R,4R)-3-amino-4-hydroxypiperidine-1-carboxylate (1.513 g, 6.05mmol) in DMF (30.2 ml) was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (3.17 g, 8.34 mmol) and N,N-diisopropylethylamine(3.16 ml, 18.14 mmol). The reaction mixture was stirred at roomtemperature for 2 h. The reaction was diluted with DCM and water, theaqueous layer was extracted with DCM once. The combined organic layerswere dried over Na₂SO₄, filtered and concentrated. The residue waspurified with flash chromatography (eluting with 0-10% ethylacetate/hexanes) to give the desired product (2.70 g, 100%). LC-MScalculated for C₂₁H₂₄BrN₂O₄ (M+H)⁺: m/z=447.1; found 447.1.

Step 2: benzyl(R)-3-(3-bromo-2-methylbenzamido)-4-oxopiperidine-1-carboxylate

To a solution of benzyl(3R,4R)-3-(3-bromo-2-methylbenzamido)-4-hydroxypiperidine-1-carboxylate(2.70 g, 6.04 mmol) in DCM (20 ml) was added Dess-Martin periodinane(3.07 g, 7.24 mmol). The resulting mixture was stirred at roomtemperature for 2 h. The reaction mixture was diluted with Et₂O and 1 MNaOH. After stirring for 1 h, The organic layer was separated and driedover Na₂SO₄, filtered and concentrated. The crude was purified by flashchromatography (eluting with 0-10% ethyl acetate/hexanes) to give thedesired product (1.84 g, 70%). LC-MS calculated for C₂₁H₂₂BrN₂O₄ (M+H)⁺:m/z=445.1; found 445.1.

Step 3: benzyl2-(3-bromo-2-methylphenyl)-6,7-dihydrooxazolo[4,5-c]pyridine-5(4H)-carboxylate

To a solution of benzyl(R)-3-(3-bromo-2-methylbenzamido)-4-oxopiperidine-1-carboxylate (1.87 g,4.20 mmol) in 1,4-dioxane (30 ml) was added POCl₃ (0.391 ml, 4.20 mmol).The resulting mixture was stirred at 110° C. for 3 h. After cooling toroom temperature, the reaction mixture was diluted with saturated NaHCO₃and ethyl acetate. The aqueous layer was extracted with ethyl acetateonce. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated. The crude was purified by flashchromatography (eluting with 0-40% ethyl acetate/hexane) to give thedesired product (1.22 g, 68%). LC-MS calculated for C₂₁H₂₀BrN₂O₃ (M+H)⁺:m/z=427.1; found 427.1.

Step 4:2-(3-bromo-2-methylphenyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine

To solution of benzyl2-(3-bromo-2-methylphenyl)-6,7-dihydrooxazolo[4,5-c]pyridine-5(4H)-carboxylate(1.15 g, 2.69 mmol) in CH₂Cl₂ (10 ml) was added 1 M BBr₃ in DCM (5.38ml, 5.38 mmol) at 0° C. After stirring at same temperature for 1 h, thereaction mixture was diluted DCM and saturated NaHCO₃ solution. Theresultant precipitate was collected vial filtration and dried undervacuum to give the desired product as white solid (0.61 g, 77%). LC-MScalculated for C₁₃H₁₄BrN₂O (M+H)⁺: m/z=293.0; found 293.0.

Step 5.(7-chloro-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanol

(1,1′-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (127 mg,0.174 mmol) was added to a mixture of2-(3-bromo-2-methylphenyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine (511mg, 1.741 mmol),(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol(Example 1, Step 5; 696 mg, 1.741 mmol), sodium carbonate (369 mg, 3.48mmol) in 1,4-dioxane (8.0 ml) and water (1.6 ml). The mixture was purgedwith N₂ and heated at 90° C. for 2 h. The mixture was diluted with ethylacetate and water. The organic layer was separated and dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography (eluting with 0-20% methanol in DCM) to give the desiredproduct (0.72 g, 85%). LC-MS calculated for C₂₈H₂₅ClN₃O₃ (M+H)⁺:m/z=486.2; found 486.2.

Step 6. tert-butyl2-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrooxazolo[4,5-c]pyridine-5(4H)-carboxylate

To a solution of(7-chloro-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanol(720 mg, 1.482 mmol) in methanol (10 ml) was added Boc-anhydride (0.344ml, 1.482 mmol). The resulting mixture was stirred at rt for 2 h. Thesolvent was removed and residue was purified by flash chromatography(eluting with 0-60% ethyl acetate in hexanes) to give the desiredproduct (0.71 g, 82%). LC-MS calculated for C₃₃H₃₃ClN₃O₅ (M+H)⁺:m/z=586.2; found 586.2.

Step 7. tert-butyl2-(3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrooxazolo[4,5-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl2-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrooxazolo[4,5-c]pyridine-5(4H)-carboxylate(710 mg, 1.211 mmol) in DCM (10 ml) was added Dess-Martin periodinane(617 mg, 1.454 mmol). The resulting mixture was stirred at rt for 2 h.The reaction mixture was diluted with Et₂O and 1 M NaOH. After stirringfor 1 h, the organic layer was separated and dried over Na₂SO₄, filteredand concentrated. The residue was purified by flash chromatography(eluting with 0-60% ethyl acetate in hexanes) to give the desiredproduct (0.70 g, 99%). LC-MS calculated for C₃₃H₃₁ClN₃O₅ (M+H)⁺:m/z=584.2; found 584.2.

Step 8:(R)-1-((7-chloro-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a mixture of tert-butyl2-(3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrooxazolo[4,5-c]pyridine-5(4H)-carboxylate(360 mg, 0.616 mmol), (R)-pyrrolidine-3-carboxylic acid (71.0 mg, 0.616mmol) and triethylamine (0.172 ml, 1.233 mmol) in CH₂Cl₂ (5.0 ml) wasadded sodium triacetoxyborohydride (131 mg, 0.616 mmol). After stirringat room temperature overnight, the reaction mixture was diluted withMeOH and then purified by prep-HPLC (pH=2, acetonitrile/water+TFA).After removing solvent, the residue was treated with 1:1 TFA/DCM (4 mL)for 1 h. The solvent was removed in vacuo. The residue was purified byprep LCMS (pH 2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₃₃H₃₂ClN₄O₄ (M+H)⁺: m/z=583.2; found583.2. ¹H NMR (500 MHz, DMSO) δ 8.18 (m, 1H), 8.03 (d, J=1.2 Hz, 1H),7.95 (m, 1H), 7.79 (d, J=1.3 Hz, 1H), 7.58 (m, 1H), 7.54-7.43 (m, 2H),7.36 (m, 1H), 4.55 (s, 2H), 4.48 (s, 2H), 3.66-3.15 (m, 7H), 2.90 (m,2H), 2.42 (s, 3H), 2.33 (s, 3H), 2.20 (m, 2H).

Example 75(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

In a microwave vial was combined(R)-1-((2-(3′-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-chlorobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (Example 74; 6.0 mg, 8.78 μmol), potassium ferrocyanide(II) hydrate(2.406 μl, 10.54 μmol),[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (0.698 mg, 0.878 μmol), potassium acetate(0.862 mg, 8.78 μmol), 1,4-dioxane (200 μl) and water (200 μl). The vialwas capped and purged with nitrogen. The reaction was heated to 100° C.for 2 hours. After cooling to RT, the reaction mixture was diluted withmethanol, passed through a syringe filter and purified by prep-HPLC(pH=2, acetonitrile/water+TFA). After removing solvent, the residue wastreated with 1:1 TFA/DCM (4 mL) for 1 h. The solvent was removed invacuo. The residue was purified by prep LCMS (pH 2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₃₄H₃₂N₅O₄ (M+H)⁺: m/z=574.2; found 574.2.

Example 76(S)-1-((7-chloro-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 74 with (S)-pyrrolidine-3-carboxylic acid replacing(R)-pyrrolidine-3-carboxylic acid in Step 8. LC-MS calculated forC₃₃H₃₂ClN₄O₄ (M+H)⁺: m/z=583.2; found 583.2.

Example 771-((7-chloro-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 74 with azetidine-3-carboxylic acid replacing(R)-pyrrolidine-3-carboxylic acid in Step 8. LC-MS calculated forC₃₂H₃₀ClN₄O₄ (M+H)⁺: m/z=569.2; found 569.2.

Example 78(R)-1-((7-chloro-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 74 with benzyl (3S,4S)-4-amino-3-hydroxypiperidine-1-carboxylatereplacing benzyl (3R,4R)-3-amino-4-hydroxypiperidine-1-carboxylate inStep 1. LC-MS calculated for C₃₃H₃₂ClN₄O₄ (M+H)⁺: m/z=583.2; found583.2.

Example 79(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(4,4,5-trimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: 2-bromo-5-methyl-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one

To solution of 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one (ArkPharm, Inc, cat #AK-38786, 250 mg, 1.073 mmol) in tetrahydrofuran (3.0mL) was added sodium hydride (60 wt % in mineral oil, 64.3 mg, 1.61mmol) at 0° C. After stirring for 30 min, methyl iodide (0.134 mL, 2.145mmol) was added to reaction mixture. The resultant mixture was stirredat rt overnight. The reaction was diluted with water and ethyl acetate.The organic layer was separated and concentrated. The residue waspurified by flash chromatography (eluting with 0-40% ethylacetate/hexanes) to give the desired product (254 mg, 96%). LC-MScalculated for C₇H₈BrN₂OS (M+H)⁺: m/z=247.0; found 246.9.

Step 2:2-(3-chloro-2-methylphenyl)-5-methyl-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one

To microwave vial was added (3-chloro-2-methylphenyl)boronic acid (175mg, 1.03 mmol),2-bromo-5-methyl-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one (254 mg,1.03 mmol), (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II)(75 mg, 0.10 mmol), sodium carbonate (218 mg, 2.05 mmol), 1,4-dioxane(6.5 ml) and water (1.300 ml). The mixture was purged with N₂ and heatedat 90° C. for 2 h. The reaction mixture was diluted with ethyl acetateand water, the organic layer was separated, washed with brine, driedover Na₂SO₄, and filtered. The filtrate was concentrated and the residuewas purified by flash chromatography (eluting with EtOAc/Hexanes 0-40%)to give the desired product (204 mg, 68%). LC-MS calculated forC₁₄H₁₄ClN₂OS (M+H)⁺: m/z=293.0; found 293.0.

Step 3:2-(3-chloro-2-methylphenyl)-4,4,5-trimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

To a solution of2-(3-chloro-2-methylphenyl)-5-methyl-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one(204 mg, 0.697 mmol), 2,6-di-tert-butyl-4-methylpyridine (172 mg, 0.836mmol) in DCM (6.0 ml) at −78° C. was added trifluoromethanesulfonicanhydride (0.141 ml, 0.836 mmol). After stirring at same temperature for1 h, methylmagnesium bromide (3 M in ether 0.557 ml, 1.672 mmol) wasadded to reaction mixture and allowed to warm to room temperature over 3h. The reaction mixture was diluted with DCM and saturated NH₄Clsolution, the organic layer was separated and dried over Na₂SO₄,filtered and concentrated. The residue was purified by flashchromatography (eluting with 0-30% ethyl acetate/hexanes) to give thedesired product (167 mg, 78%). LC-MS calculated for C₁₆H₂₀ClN₂S (M+H)⁺:m/z=307.1; found 307.1.

Step 4:4,4,5-trimethyl-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

To a microwave vial was charged with2-(3-chloro-2-methylphenyl)-4,4,5-trimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine(151 mg, 0.492 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (125 mg,0.492 mmol), tris(dibenzylideneacetone)dipalladium(0) (18.03 mg, 0.020mmol), 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl(37.5 mg, 0.079 mmol) and potassium acetate (145 mg, 1.476 mmol). Thevial was sealed and evacuated under high vacuum and refilled withnitrogen (this process was repeated three times). 1,4-dioxane (2 mL) wasadded. The mixture was stirred at 100° C. for 5 h. After cooling to roomtemperature, the mixture was diluted with ethyl acetate and filtered.The filtrate was concentrated in vacuo and the residue was purified byflash chromatography (eluting with 0-20% methanol in DCM) to give thedesired product (160 mg, 82%). LC-MS calculated for C₂₂H₃₂BN₂O₂S (M+H)⁺:m/z=399.2; found 399.2.

Step 5:7-chloro-2-(2,2′-dimethyl-3′-(4,4,5-trimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-5-carbaldehyde

To a microwave vial was charged with4,4,5-trimethyl-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine(90 mg, 0.225 mmol),2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazole-5-carbaldehyde(Example 10, Step 1; 79 mg, 0.225 mmol),(1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (16.5 mg,0.023 mmol), sodium carbonate (47.8 mg, 0.451 mmol) in 1,4-dioxane (2.0ml) and water (0.400 ml). The mixture was purged with N₂ and heated at90° C. for 2 h. The mixture was diluted with ethyl acetate and water,the organic layer was separated, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography (elutingwith 0-20% methanol in DCM) to give the desired product (94 mg, 77%).LC-MS calculated for C₃₁H₂₉ClN₃O₂S (M+H)⁺: m/z=542.2; found 542.2.

Step 6:(R)-1-((7-chloro-2-(2,2′-dimethyl-3′-(4,4,5-trimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Sodium triacetoxyborohydride (12.5 mg, 0.059 mmol) was added to amixture of7-chloro-2-(2,2′-dimethyl-3′-(4,4,5-trimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-5-carbaldehyde(32 mg, 0.059 mmol), (R)-pyrrolidine-3-carboxylic acid (6.80 mg, 0.059mmol) in DCM (1.0 ml) at room temperature. After stirring at rtovernight, The solvent was removed in vacuo and the residue was purifiedwith prep LCMS (pH 2, acetonitrile/water+TFA) to give the desiredproduct as TFA salt. LC-MS calculated for C₃₆H₃₈ClN₄O₃S (M+H)⁺:m/z=641.2; found 641.2.

Step 7:(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(4,4,5-trimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 73 with(R)-1-((7-chloro-2-(2,2′-dimethyl-3′-(4,4,5-trimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid replacing(R)-1-((7-chloro-2-(2,2′-dimethyl-3′-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid. LC-MS calculated for C₃₇H₃₈N₅O₃S (M+H)⁺: m/z=632.3; found 632.2.

Example 80(R)-1-((7-cyano-2-(3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 36 with (R)-pyrrolidine-3-carboxylic acid replacing(S)-pyrrolidine-3-carboxylic acid in Step 7. The reaction was dilutedwith MeOH and then purified by prep-HPLC (pH=2, acetonitrile/water+TFA)to give the desired product as TFA salt. LC-MS calculated for C₃₇H₃₈N₇O₄(M+H)⁺: m/z=644.3; found 644.3.

Example 81(S)-1-((7-chloro-2-(2′-chloro-3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 29 with (R)-pyrrolidin-3-ol replacing (S)-pyrrolidin-3-ol inStep 4 and (S)-pyrrolidine-3-carboxylic acid replacing(R)-pyrrolidine-3-carboxylic acid in Step 7. The reaction was dilutedwith MeOH and then purified by prep-HPLC (pH=10,acetonitrile/water+NH₄OH) to give the desired product. LC-MS calculatedfor C₃₉H₃₇Cl₂N₆O₄ (M+H)⁺: m/z=723.2; found 723.2.

Example 82(R)-1-((7-chloro-2-(2′-chloro-3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 29 with (R)-pyrrolidin-3-ol replacing (S)-pyrrolidin-3-ol inStep 4. The reaction was diluted with MeOH and then purified byprep-HPLC (pH=10, acetonitrile/water+NH₄OH) to give the desired product.LC-MS calculated for C₃₉H₃₇Cl₂N₆O₄ (M+H)⁺: m/z=723.2; found 723.2.

Example 83(S)-1-((2-(2′-chloro-3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 30 with (S)-pyrrolidine-3-carboxylic acid replacing(R)-pyrrolidine-3-carboxylic acid and (R)-pyrrolidin-3-ol replacing(S)-pyrrolidin-3-ol. The reaction was diluted with MeOH and thenpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as TFA salt. LC-MS calculated for C₄₀H₃₇ClN₇O₄ (M+H)⁺:m/z=714.3; found 714.3.

Example 84(R)-1-((2-(2′-chloro-3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 30 with (R)-pyrrolidin-3-ol replacing (S)-pyrrolidin-3-ol. Thereaction was diluted with MeOH and then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₄₀H₃₇ClN₇O₄ (M+H)⁺: m/z=714.3; found 714.3.

Example 85(R)-1-((7-cyano-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 24 with azetidine-3-carboxylic acid replacing(R)-pyrrolidine-3-carboxylic acid in Step 5. The reaction mixture wasdiluted with MeOH and then purified by prep-HPLC (pH=10,acetonitrile/water+NH₄OH) to give the desired product. LC-MS calculatedfor C₄₀H₃₈N₇O₄ (M+H)⁺: m/z=680.3; found 680.3.

Example 86(R)-3-((7-cyano-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methylamino)-2,2-dimethylpropanoicAcid

This compound was prepared using similar procedures as described forExample 24 with 3-amino-2,2-dimethylpropanoic acid replacing(R)-pyrrolidine-3-carboxylic acid in Step 5. The reaction mixture wasdiluted with MeOH and then purified by prep-HPLC (pH=10,acetonitrile/water+NH₄OH) to give the desired product. LC-MS calculatedfor C₄₁H₄₂N₇O₄ (M+H)⁺: m/z=696.3; found 696.3.

Example 87(R)-1-((2-(2′-chloro-3′-(6-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:(R)-1-((2-(2′-chloro-2-methyl-3′-(4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar method in Example 54, Step 1-6with tert-butyl1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate (Astatech,cat #79248) replacing tert-butyl1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate in Step 1.The reaction mixture was concentrated and used in next step withoutfurther purification. LC-MS calculated for C₃₃H₃₀ClN₆O₃ (M+H)⁺:m/z=593.2; found 593.1.

Step 2:(R)-1-((2-(2′-chloro-3′-(6-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of(R)-1-((2-(2′-chloro-2-methyl-3′-(4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (10 mg, 0.017 mmol) and acetone (2.4 μL, 0.034 mmol) in DCM (169μl) was allowed to stir for 2 h. Then sodium triacetoxyborohydride (7.0mg, 0.034 mmol) was added to the mixture. After 2 h, the mixture wasconcentrated and diluted with MeOH and then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₃₆H₃₆ClN₆O₃ (M+H)⁺: m/z=635.2; found 635.3. ¹H NMR(500 MHz, DMSO) δ 8.21 (d, J=6.7 Hz, 1H), 8.13 (s, 1H), 7.89 (s, 1H),7.86 (s, 1H), 7.64-7.55 (m, 3H), 7.50 (d, J=6.4 Hz, 1H), 7.45 (dd,J=7.1, 2.1 Hz, 1H), 3.85-3.68 (m, 3H), 3.62 (s, 2H), 2.99-2.87 (m, 2H),2.79-2.58 (m, 5H), 2.58-2.52 (m, 2H), 2.49 (s, 3H), 1.98 (q, J=7.1 Hz,2H), 1.08 (d, J=6.6 Hz, 6H).

Example 88(R)-1-((2-(2′-chloro-3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 50 with (R)-3-methylpyrrolidine-3-carboxylic acid replacing(S)-pyrrolidine-3-carboxylic acid in Step 6. The reaction was dilutedwith MeOH and then purified by prep-HPLC (pH=2, acetonitrile/water+TFA)to give the desired product as TFA salt. LC-MS calculated forC₃₇H₃₇ClN₇O₄ (M+H)⁺: m/z=678.3; found 678.3. ¹H NMR (500 MHz, DMSO) δ9.97 (s, 1H), 8.40 (d, J=1.2 Hz, 1H), 8.24 (dd, J=8.2, 1.3 Hz, 1H), 8.21(d, J=7.0 Hz, 1H), 8.13 (d, J=1.2 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.52(t, J=7.9 Hz, 1H), 7.48 (d, J=6.8 Hz, 1H), 7.20 (dd, J=7.6, 1.4 Hz, 1H),4.59 (s, 2H), 4.52-4.11 (m, 2H), 3.95 (s, 3H), 3.87-3.26 (m, 6H),3.08-3.00 (m, 2H), 2.95 (s, 3H), 2.46 (s, 3H), 2.38-1.79 (m, 2H), 1.37(s, 3H).

Example 891-((2-(2′-chloro-3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylicAcid

This compound was prepared using similar procedures as described forExample 50 with piperidine-4-carboxylic acid replacing(S)-pyrrolidine-3-carboxylic acid in Step 6. The reaction was dilutedwith MeOH and then purified by prep-HPLC (pH=2, acetonitrile/water+TFA)to give the desired product as TFA salt. LC-MS calculated forC₃₇H₃₇ClN₇O₄ (M+H)⁺: m/z=678.3; found 678.3. ¹H NMR (600 MHz, DMSO) δ9.97 (s, 1H), 8.37 (s, 1H), 8.24 (dd, J=8.2, 1.5 Hz, 1H), 8.23-8.20 (m,1H), 8.10 (s, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 7.49(dd, J=7.6, 1.0 Hz, 1H), 7.21 (dd, J=7.6, 1.5 Hz, 1H), 4.66-4.37 (m,3H), 4.21 (s, 1H), 3.95 (s, 3H), 3.84-3.27 (m, 4H), 3.09-2.98 (m, 4H),2.95 (s, 3H), 2.49 (m, 1H), 2.46 (s, 3H), 2.13-1.64 (m, 4H).

Example 90(S)-2-((2-(2′-chloro-3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methylamino)propanoicAcid

This compound was prepared using similar procedures as described forExample 50 with (S)-2-aminopropanoic acid replacing(S)-pyrrolidine-3-carboxylic acid in Step 6. The reaction was dilutedwith MeOH and then purified by prep-HPLC (pH=2, acetonitrile/water+TFA)to give the desired product as TFA salt. LC-MS calculated forC₃₄H₃₃ClN₇O₄ (M+H)⁺: m/z=638.2; found 638.2.

Example 91(1R,4R)-4-((2-(2′-chloro-3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methylamino)cyclohexanecarboxylicAcid

This compound was prepared using similar procedures as described forExample 50 with (1R,4R)-4-aminocyclohexanecarboxylic acid replacing(S)-pyrrolidine-3-carboxylic acid in Step 6. The reaction was dilutedwith MeOH and then purified by prep-HPLC (pH=2, acetonitrile/water+TFA)to give the desired product as TFA salt. LC-MS calculated forC₃₈H₃₉ClN₇O₄ (M+H)⁺: m/z=692.3; found 692.3.

Example 92(S)-1-((2-(2′-chloro-2-methyl-3′-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: tert-butyl2-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

A mixture of tert-butyl2-(3-bromo-2-chlorophenylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(Example 50, Step 1: 8.01 g, 17.03 mmol),(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol(Example 1, Step 5: 7.49 g, 18.73 mmol), anddichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II) (1.39 g,1.70 mmol) in 1,4-dixoane (95 mL) and water (19 mL) was added sodiumcarbonate (3.61 g, 34.10 mmol). The reaction mixture was purged withnitrogen and then stirred at 100° C. for 36 hrs. After being cooled toroom temperature, the reaction mixture was extracted with ethyl acetate.The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column eluting with 0to 70% EtOAc in hexanes to afford the desired product. LC-MS calculatedfor C₃₄H₃₄Cl₂N₅O₅ (M+H)⁺: m/z=662.2; found 662.2.

Step 2: tert-butyl2-(2-chloro-3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

This compound was prepared using similar procedures as described forExample 12 with tert-butyl2-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylatereplacing(7-chloro-2-(2,2′-dimethyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanolin Step 1. LC-MS calculated for C₃₅H₃₄ClN₆O₅ (M+H)⁺: m/z=653.2; found653.2.

Step 3: tert-butyl2-(2-chloro-3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

A suspension of tert-butyl2-(2-chloro-3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(3.56 g, 6.28 mmol) and manganese dioxide (10.92 g, 126 mmol) in DCM (60mL) was stirred at 45° C. for 3 hrs. The reaction was filtered through ashort pad of celite and then concentrated to yield a crude residue,which was used directly without further purification. LC-MS calculatedfor C₃₅H₃₂ClN₆O₅ (M+H)⁺: m/z=651.2; found 651.2

Step 4:(S)-1-((2-(3′-(5-(tert-butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2′-chloro-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution of tert-butyl2-(2-chloro-3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(100 mg, 0.153 mmol) in DCM (6 ml) was added(S)-pyrrolidine-3-carboxylic acid (26.5 mg, 0.230 mmol) and TEA (0.085ml, 0.614 mmol). The mixture was stirred at r.t. for 60 min, then sodiumtriacetoxyborohydride (48.8 mg, 0.23 mmol) was added. The resultingmixture was stirred at r.t. overnight then concentrated. The residue waspurified via prep-HPLC (pH=2, MeCN/water with TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₄₀H₄₁ClN₇O₆ (M+H)⁺:m/z=750.3; found 750.3.

Step 5:(S)-1-((2-(2′-chloro-2-methyl-3′-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution of(S)-1-((2-(3′-(5-(tert-butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2′-chloro-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (50 mg, 0.067 mmol) in DCM (1 mL) was added trifluoroacetic acid (1mL) and MeOH (0.013 mL). The solution was stirred at r.t. for 1 h. thenconcentrate. The residue was purified via prep-HPLC (pH=2, MeCN/waterwith TFA) to give the desired product as the TFA salt. LC-MS calculatedfor C₃₅H₃₃ClN₇O₄ (M+H)⁺: m/z=650.3; found 650.3.

Example 93(S)-1-((2-(2′-chloro-3′-(5-(2-hydroxyethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution of(S)-1-((2-(2′-chloro-2-methyl-3′-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (Example 92, Step 5: 20 mg, 0.031 mmol) in DCM (0.5 ml) was added2-(tert-butyldimethylsilyloxy)acetaldehyde (9.8 mg, 0.046 mmol). Themixture was stirred at r.t. for 60 min, then sodiumtriacetoxyborohydride (6.4 mg, 0.037 mmol) was added. After beingstirred at room temperature for 2 hrs, 2 N HCl solution in water (0.2mL) was added, and the reaction was stirred at 50° C. for 30 min. Thereaction mixture was diluted with MeOH, and purified via pH 2preparative HPLC (MeCN/water with TFA) to give the desired product asTFA salt. LC-MS calculated for C₃₇H₃₇ClN₇O₅ (M+H)⁺: m/z=694.3; found694.3.

Example 94(S)-1-((2-(2′-chloro-3′-(1,5-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: 5-tert-butyl 2-ethyl3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate

To a solution of cis-tert-butyl 3,4-diaminopyrrolidine-1-carboxylate(Pharmablock, cat #PB05568: 800 mg, 3.97 mmol) in HFIP (5 mL) was addedethyl 2-ethoxy-2-iminoacetate (577 mg, 3.97 mmol). The mixture wasstirred at 50° C. for overnight before quenched by adding sat. NaClsolution. Then 1N HCl was added to adjust the pH to 1, which was thenextracted with EtOAc for 3 times. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography on asilica gel column eluting with 0 to 10% MeOH in DCM to afford thedesired product. LC-MS calculated for C₁₃H₂₂N₃O₄ (M+H)⁺: m/z=284.3;found 284.3.

Step 2: 5-tert-butyl 2-ethyl1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate

To a solution of oxalyl chloride (0.13 mL, 1.48 mmol) in DCM (4 mL) wasslowly added DMSO (0.21 mL, 2.96 mmol) for 30 mins. The resultingsolution was added DCM solution of 5-tert-butyl 2-ethyl3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate (210mg, 0.74 mmol) dropwise. After adding, the solution was stirred for 30mins before DIEA (0.86 mL, 4.94 mmol) was added. The reaction mixturewas warmed to r.t. over 2 hrs, which was then quenched by adding sat.NH₄Cl. The mixture was extracted with DCM for 3 times. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was dissolved in DMF (3mL), K₂CO₃ (273 mg, 1.97 mmol) and methyl iodide (0.12 mL, 1.97 mmol)were added sequentially. The resulting mixture was stirred at r.t.overnight before 3 mL of water was added. The mixture was extracted withEtOAc for 3 times. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel columneluting with 0 to 100% EtOAc in hexanes to afford the desired product.LC-MS calculated for C₁₄H₂₂N₃O₄ (M+H)⁺: m/z=296.2; found 296.2.

Step 3: tert-butyl2-(3-bromo-2-chlorophenylcarbamoyl)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

Potassium tert-butoxide in THF (1.0 M, 2.13 mL) was added to a solutionof 5-tert-butyl 2-ethyl4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate (400 mg, 1.42mmol) and 3-bromo-2-chloroaniline (323 mg, 1.56 mmol) in THF (12.0 mL).After being stirred at room temperature for 1 h, the reaction mixturewas quenched with water, and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column eluting with 100% ethyl acetate inhexanes to afford the desired product. LCMS calculated forC₁₈H₂₁BrClN₄O₃ (M+H)⁺: m/z=457.0; found 457.0.

Step 4: tert-butyl2-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

A mixture tert-butyl2-(3-bromo-2-chlorophenylcarbamoyl)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate(150 mg, 0.33 mmol),(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol(Example 1, Step 5: 158 mg, 0.39 mmol), anddichloro[1,1′-bis(dicyclohexylphosphino)ferrocene] palladium(II) (27 mg,0.033 mmol) in 1,4-dioxane (5 ml) and water (1 mL) was added sodiumcarbonate (70 mg, 0.66 mmol). The reaction mixture was purged withnitrogen and then stirred at 100° C. for 12 hrs. After being cooled toroom temperature, the reaction mixture was extracted with ethyl acetate.The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column eluting with 0to 100% EtOAc in hexanes to afford the desired product. LC-MS calculatedfor C₃₃H₃₂Cl₂N₅O₅ (M+H)⁺: m/z=648.2; found 648.2.

Step 5: tert-butyl2-(2-chloro-3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

This compound was prepared using similar procedures as described forExample 12 with tert-butyl2-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylatereplacing(7-chloro-2-(2,2′-dimethyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanolin Step 1. LC-MS calculated for C₃₄H₃₂ClN₆O₅ (M+H)⁺: m/z=639.2; found639.2.

Step 6: tert-butyl2-(2-chloro-3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

A suspension of tert-butyl2-(2-chloro-3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate(20 mg, 0.03 mmol) and manganese dioxide (54 mg, 0.63 mmol) in DCM (6mL) was stirred at 45° C. for 3 hrs. The reaction was filtered through ashort pad of celite and then concentrated to yield a crude residue,which was used directly without further purification. LC-MS calculatedfor C₃₄H₃₀ClN₆O₅ (M+H)⁺: m/z=637.2; found 637.2.

Step 7:(S)-1-((2-(3′-(5-(tert-butoxycarbonyl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamido)-2′-chloro-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution tert-butyl2-(2-chloro-3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate(15.0 mg, 0.024 mmol) in DCM (0.5 ml) was added(S)-pyrrolidine-3-carboxylic acid (6.5 mg, 0.047 mmol) and TEA (0.013ml, 0.094 mmol). The mixture was stirred at r.t. for 60 min, then sodiumtriacetoxyborohydride (7.5 mg, 0.035 mmol) was added. The resultingmixture was stirred at r.t. overnight then concentrated. The residue waspurified via prep-HPLC (pH=2, MeCN/water with TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₃₉H₃₉ClN₇O₆ (M+H)⁺:m/z=736.3; found 736.3.

Step 8:(S)-1-((2-(2′-chloro-3′-(1,5-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution of(S)-1-((2-(3′-(5-(tert-butoxycarbonyl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamido)-2′-chloro-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (10 mg, 0.014 mmol) in DCM (1 mL) was added trifluoroacetic acid (1mL). The solution was stirred at r.t. for 1 h. then concentrate todryness. The residue was dissolved in DCM (1.0 mL) then formaldehyde (37wt % in water, 0.02 mL) was added. The resulting mixture was stirred atr.t. for 10 min, then sodium triacetoxyborohydride (5.8 mg, 0.027 mmol)was added. The reaction mixture was stirred at r.t. overnight thenconcentrated. The residue was purified via prep-HPLC (pH=2, MeCN/waterwith TFA) to give the desired product as the TFA salt. LC-MS calculatedfor C₃₅H₃₃ClN₇O₄ (M+H)⁺: m/z=650.3; found 650.3.

Example 95(R)-1-((2-(2′-chloro-3′-(5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicAcid

Step 1:(R)-1-((2-(3′-(5-(tert-butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2′-chloro-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicAcid

To a solution of tert-butyl2-(2-chloro-3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(Example 92, step 3: 25 mg, 0.043 mmol) in DCM (1 mL) was added(R)-3-methylpyrrolidine-3-carboxylic acid (7.7 mg, 0.056 mmol) and TEA(0.02 ml, 0.16 mmol). The mixture was stirred at r.t. for 60 min, thensodium triacetoxyborohydride (12.2 mg, 0.056 mmol) was added. Theresulting mixture was stirred at r.t. overnight then concentrated. Theresidue was purified via prep-HPLC (pH=2, MeCN/water with TFA) to givethe desired product as the TFA salt. LC-MS calculated for C₄₁H₄₃ClN₇O₆(M+H)⁺: m/z=764.3; found 764.3.

Step 2:(R)-1-((2-(2′-chloro-3′-(5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicAcid

To a solution of(S)-1-((2-(3′-(5-(tert-butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2′-chloro-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (10 mg, 0.013 mmol) in DCM (1 mL) was added trifluoroacetic acid (1mL). The solution was stirred at r.t. for 1 h. then concentrate todryness. The residue was dissolved in DCM (1.0 mL) then acetaldehyde(3.0 mg, 0.065 mmol) was added. The resulting mixture was stirred atr.t. for 10 min, then sodium triacetoxyborohydride (5.8 mg, 0.027 mmol)was added. The reaction mixture was stirred at r.t. overnight thenconcentrated. The residue was purified via prep-HPLC (pH=2, MeCN/waterwith TFA) to give the desired product as the TFA salt. LC-MS calculatedfor C₃₈H₃₉ClN₇O₄ (M+H)⁺: m/z=692.3; found 692.3. ¹H NMR (600 MHz, DMSO)δ 9.95 (s, 1H), 8.39 (d, J=1.4 Hz, 1H), 8.28 (dd, J=8.2, 1.5 Hz, 1H),8.21 (dd, J=7.9, 1.2 Hz, 1H), 8.13 (d, J=1.4 Hz, 1H), 7.59 (t, J=7.7 Hz,1H), 7.52 (t, J=7.9 Hz, 1H), 7.48 (dd, J=7.6, 1.1 Hz, 1H), 7.20 (dd,J=7.6, 1.5 Hz, 1H), 4.59 (s, 2H), 4.52-4.14 (m, 2H), 3.95 (s, 3H),3.88-3.24 (m, 8H), 3.03 (m, 2H), 2.46 (s, 3H), 2.39-1.79 (m, 2H), 1.38(s, 3H), 1.30 (t, J=7.3 Hz, 3H).

Example 96(R)-1-((7-cyano-2-(3′-(3-(1-(2-hydroxyethyl)azetidin-3-yl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: tert-butyl3-(8-chloro-1,7-naphthyridin-3-yl)azetidine-1-carboxylate

To a long, thin (˜20 mL) borosilicate glass vial equipped with aTeflon-coated magnetic stir bar was added4,7-di-tert-butyl-1,10-phenanthroline (12.01 mg, 0.041 mmol) andNiCl₂.glyme (9.02 mg, 0.041 mmol) and 1.0 mL THF. The vial was cappedand the resulting suspension was heated briefly with a heat gun untilthe nickel and ligand were fully solubilized, yielding a pale greensolution. The solvent was then removed under vacuum to give a finecoating of the ligated nickel complex (pale evergreen in color). Oncedry, 3-bromo-8-chloro-1,7-naphthyridine (100 mg, 0.411 mmol), tert-butyl3-(trifluoro-l4-boranyl)azetidine-1-carboxylate, potassium salt(Combi-Blocks, cat #QC-6288: 108 mg, 0.411 mmol),[Ir{dFCF₃ppy}₂(bpy)]PF₆ (Aldrich, cat #804215: 10.37 mg, 10.27 μmol) andcesium carbonate (201 mg, 0.616 mmol) were added in succession. The vialwas then capped and purged and evacuated four times. Under inertatmosphere, 1,4-dioxane (10 mL) was introduced. The vial containing allthe reagents was further sealed with parafilm and stirred for 24 hrsapproximately 4 cm away from two 26 W fluorescent light bulbs. Thereaction mixture was then concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel columneluting with 0 to 100% EtOAc in hexanes to afford the desired product.LC-MS calculated for C₁₆H₁₉ClN₃O₂ (M+H)⁺: m/z=320.2; found 320.2.

Step 2: tert-butyl3-(8-(3-bromo-2-methylphenylamino)-1,7-naphthyridin-3-yl)azetidine-1-carboxylate

A mixture of 3-bromo-2-methylaniline (31.4 mg, 0.169 mmol), tert-butyl3-(8-chloro-1,7-naphthyridin-3-yl)azetidine-1-carboxylate (45 mg, 0.141mmol) and sulfuric acid (7.50 μl, 0.141 mmol) in isopropanol (10 ml) washeated at 90° C. for 2 h. The reaction was then cooled to roomtemperature and diluted with DCM. The reaction was quenched by aqueousNaHCO₃ solution, extracted with DCM. The organic phase was dried overMgSO₄, filtered and the filtrate was concentrated. The residue wasdissolved in DCM (2 mL), di-tert-butyl dicarbonate (123 mg 0.56 mmol)and TEA (57.0 mg, 0.56 mmol) were added subsequently. The resultingreactions mixture was allowed to stir for 2 hrs before quenched withsat. NaHCO₃. The mixture was then extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column eluting with 0to 100% EtOAc in hexanes to afford the desired product. LC-MS calculatedfor C₂₃H₂₆BrN₄O₂ (M+H)⁺: m/z=469.1/471.1; found 469.2/471.2.

Step 3: tert-butyl3-(8-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)azetidine-1-carboxylate

A mixture of tert-butyl3-(8-(3-bromo-2-methylphenylamino)-1,7-naphthyridin-3-yl)azetidine-1-carboxylate(39.1 mg, 0.083 mmol),(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol(Example 1, Step 5: 40 mg, 0.10 mmol), sodium carbonate (24 mg, 0.22mmol) and tetrakis(triphenylphosphine)palladium(0) (10 mg, 8.9 μmol) ina mixed water (150 μl) and 1,4-dioxane (750 μl) was purged with N₂ andthen stirred at 100° C. for 2 h. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate and then washed with H₂O. Theorganic layer was dried MgSO₄, filtered and concentrated to give a cruderesidue, which was purified by flash chromatography on a silica gelcolumn eluting with 0 to 10% MeOH/DCM to give the desired product. LC-MScalculated for C₃₈H₃₇ClN₅O₄ (M+H)⁺: m/z=662.3; found 662.3.

Step 4: tert-butyl3-(8-(3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)azetidine-1-carboxylate

This compound was prepared using similar procedures as described forExample 12 with tert-butyl3-(8-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)azetidine-1-carboxylatereplacing(7-chloro-2-(2,2′-dimethyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanolin Step 1. LC-MS calculated for C₃₉H₃₇N₆O₄ (M+H)⁺: m/z=653.3; found653.3.

Step 5: tert-butyl3-(8-(3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)azetidine-1-carboxylate

A suspension of tert-butyl3-(8-(3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)azetidine-1-carboxylate(59 mg, 0.09 mmol) and manganese dioxide (216 mg, 2.42 mmol) in DCM (6mL) was stirred at 45° C. for 3 hrs. The reaction was filtered through ashort pad of celite and then concentrated to yield a crude residue,which was used directly without further purification. LC-MS calculatedfor C₃₉H₃₅N₆O₄ (M+H)⁺: m/z=651.3; found 651.3.

Step 6:(R)-1-((2-(3′-(3-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution tert-butyl3-(8-(3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)azetidine-1-carboxylate(20 mg, 0.03 mmol) in DCM (1 ml) was added (R)-pyrrolidine-3-carboxylicacid (5.3 mg, 0.05 mmol) and TEA (0.008 ml, 0.061 mmol). The mixture wasstirred at r.t. for 60 min, then sodium triacetoxyborohydride (9.8 mg,0.046 mmol) was added. The resulting mixture was stirred at r.t.overnight then concentrated. The residue was purified via prep-HPLC(pH=2, MeCN/water with TFA) to give the desired product as the TFA salt.LC-MS calculated for C₄₄H₄₄N₇O₅ (M+H)⁺: m/z=750.3; found 750.3.

Step 7:(R)-1-((7-cyano-2-(3′-(3-(1-(2-hydroxyethyl)azetidin-3-yl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution of(R)-1-((2-(3′-(3-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (10 mg, 0.013 mmol) in DCM (1 mL) was added trifluoroacetic acid (1mL). The solution was stirred at r.t. for 1 h. then concentrate todryness. The residue was dissolved in DCM (1.0 mL), and2-(tert-butyldimethylsilyloxy)acetaldehyde (9.8 mg, 0.046 mmol) wasadded and. The mixture was stirred at r.t. for 60 min, then sodiumtriacetoxyborohydride (6.4 mg, 0.037 mmol) was added. After beingstirred at room temperature for 2 hrs, 2 N HCl solution in water (0.2mL) was added, and the reaction was stirred at 50° C. for 30 min. Thereaction mixture was diluted with MeOH, and purified via pH=2preparative HPLC (MeCN/water with TFA) to give the desired product asTFA salt. LC-MS calculated for C₄₁H₄₀N₇O₄ (M+H)⁺: m/z=694.3; found694.3.

Example 97(3R)-1-((2-(2′-chloro-2-methyl-3′-(3-(pyrrolidin-2-yl)-1,7-naphthyridin-8-ylamino)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: tert-butyl4-(8-chloro-1,7-naphthyridin-3-yl)-4-oxobutylcarbamate

To a solution of n-butyllithium (2.0 M in cyclohexane, 0.41 mL, 0.821mmol) in THF (40 ml) was added 3-bromo-8-chloro-1,7-naphthyridine (100mg, 0.411 mmol) dropwise at −78° C. After stirring at −78° C. for 1 h,tert-butyl 2-oxopyrrolidine-1-carboxylate (Aldrich, cat #464856: 0.140ml, 0.821 mmol) was added. After stirring for 2 h, the mixture wasquenched by sat. NH₄Cl, extracted by DCM for 3 times. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column eluting with 0-100% ethyl acetatein hexanes to afford the desired product. LCMS calculated forC₁₇H₂₁ClN₃O₃ (M+H)⁺: m/z=350.1; found 350.1.

Step 2: tert-butyl2-(8-(3-bromo-2-chlorophenylamino)-1,7-naphthyridin-3-yl)pyrrolidine-1-carboxylate

To a reaction vial, 3-bromo-2-chloroaniline (85 mg, 0.412 mmol) andtert-butyl 4-(8-chloro-1,7-naphthyridin-3-yl)-4-oxobutylcarbamate (120mg, 0.343 mmol) were suspended in isopropanol (10 ml). Sulfuric acid(0.018 ml, 0.343 mmol) was added to the reaction mixture. The resultingmixture was heated to 100° C. for 2 hrs then concentrate to dryness. Theresidue was dissolved in DCM (1.0 mL), TEA (0.1 mL, 0.68 mmol) andsodium triacetoxyborohydride (145 mg, 0.68 mmol) were added and. Themixture was stirred at r.t. for overnight before quenched with sat.NaHCO₃. The mixture was then extracted with DCM. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was dissolved in DCM (2mL), di-tert-butyl dicarbonate used (123 mg 0.56 mmol) and TEA (57.0 mg,0.56 mmol) were added subsequently. The resulting reactions mixture wasallowed to stir for 2 hrs before quenched with sat. NaHCO₃. The mixturewas then extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography on asilica gel column eluting with 0 to 100% EtOAc in hexanes to afford thedesired product. LC-MS calculated for C₂₃H₂₅BrClN₄O₂ (M+H)⁺: m/z=503.1;found 503.1.

Step 3: tert-butyl2-(8-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)pyrrolidine-1-carboxylate

A mixture ofN-(3-bromo-2-chlorophenyl)-3-(pyrrolidin-2-yl)-1,7-naphthyridin-8-amine(30 mg, 0.075 mmol),(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol(Example 1, Step 5: 38 mg, 0.075 mmol), sodium carbonate (16 mg, 0.15mmol) and tetrakis(triphenylphosphine)palladium(0) (8.7 mg, 7.5 μmol) ina mixed water (150 μl) and 1,4-dioxane (750 μl) was purged with N₂ andthen stirred at 100° C. for 2 hrs. The reaction mixture was cooled toroom temperature, diluted with ethyl acetate and then washed with H₂O.The organic layer was dried over MgSO₄, filtered and concentrated togive a crude residue, which was purified by flash chromatography on asilica gel column eluting with 0 to 100% EtOAc in hexanes to give thedesired product. LC-MS calculated for C₃₈H₃₆Cl₂N₅O₄ (M+H)⁺: m/z=696.2;found 696.2.

Step 4: tert-butyl2-(8-(2-chloro-3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)pyrrolidine-1-carboxylate

This compound was prepared using similar procedures as described forExample 12 with tert-butyl2-(8-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)pyrrolidine-1-carboxylatereplacing(7-chloro-2-(2,2′-dimethyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanolin Step 1. LC-MS calculated for C₃₉H₃₆ClN₆O₄ (M+H)⁺: m/z=687.2; found687.2.

Step 5: tert-butyl2-(8-(2-chloro-3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)pyrrolidine-1-carboxylate

A suspension of tert-butyl2-(8-(2-chloro-3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)pyrrolidine-1-carboxylate(40 mg, 0.06 mmol) and manganese dioxide (216 mg, 2.42 mmol) in DCM (6mL) was stirred at 45° C. for 3 hrs. The reaction was filtered through ashort pad of celite and then concentrated to yield a crude residue,which was used directly without further purification. LC-MS calculatedfor C₃₉H₃₄ClN₆O₄ (M+H)⁺: m/z=685.2; found 685.2.

Step 6:(3R)-1-((2-(2′-chloro-2-methyl-3′-(3-(pyrrolidin-2-yl)-1,7-naphthyridin-8-ylamino)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution tert-butyl2-(8-(2-chloro-3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)pyrrolidine-1-carboxylate(20 mg, 0.03 mmol) in DCM (1 ml) was added (R)-pyrrolidine-3-carboxylicacid (5.3 mg, 0.05 mmol) and TEA (0.008 ml, 0.061 mmol). The mixture wasstirred at r.t. for 60 min, then sodium triacetoxyborohydride (9.8 mg,0.046 mmol) was added. The resulting mixture was stirred at r.t.overnight then concentrated. The residue was dissolved in DCM (1 mL) andtrifluoroacetic acid (1 mL). The solution was stirred at r.t. for 1 h.then concentrate. The residue was purified via prep-HPLC (pH=2,MeCN/water with TFA) to give the desired product as the TFA salt. LC-MScalculated for C₃₉H₃₅ClN₇O₃ (M+H)⁺: m/z=684.2; found 684.2.

Example 98(3R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(3-(pyrrolidin-2-yl)-1,7-naphthyridin-8-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: tert-butyl2-(8-(3-bromo-2-methylphenylamino)-1,7-naphthyridin-3-yl)pyrrolidine-1-carboxylate

This compound was prepared using similar procedure as described forExample 97 with 3-bromo-2-methylaniline replacing3-bromo-2-chloroaniline in step 2. The enantiopure compounds wereobtained by chiral HPLC separation. The enantiopure compound (Peak 1compound) that was eluted first in the chromatography was used for nextreactions. LC-MS calculated for C₂₄H₂₈BrN₄O₂ (M+H)⁺: m/z=483.1, 485.1;found 483.1, 485.1.

Step 2:(3R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(3-(pyrrolidin-2-yl)-1,7-naphthyridin-8-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 97 with tert-butyl2-(8-(3-bromo-2-methylphenylamino)-1,7-naphthyridin-3-yl)pyrrolidine-1-carboxylatereplacing tert-butyl2-(8-(3-bromo-2-chlorophenylamino)-1,7-naphthyridin-3-yl)pyrrolidine-1-carboxylatein Step 3. The reaction mixture was diluted with MeOH and then purifiedby prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired productas TFA salt. LC-MS calculated for C₄₀H₃₈N₇O₃ (M+H)⁺: m/z=664.3; found664.3. ¹H NMR (600 MHz, DMSO) δ 9.04 (s, 1H), 8.48 (s, 1H), 8.39 (d,J=1.2 Hz, 1H), 8.19 (dd, J=7.9, 1.1 Hz, 2H), 8.12 (d, J=1.3 Hz, 1H),8.02 (s, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.47 (d, J=6.6 Hz, 1H), 7.41 (t,J=7.8 Hz, 1H), 7.23 (d, J=6.1 Hz, 1H), 7.05 (s, 1H), 4.95-4.81 (m, 1H),4.58 (s, 2H), 3.81-3.16 (m, 7H), 2.57-2.50 (m, 1H), 2.48 (s, 3H),2.29-2.07 (m, 5H), 2.05 (s, 3H).

Example 99(3R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(3-(pyrrolidin-2-yl)-1,7-naphthyridin-8-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: tert-butyl2-(8-(3-bromo-2-methylphenylamino)-1,7-naphthyridin-3-yl)pyrrolidine-1-carboxylate

This compound was prepared using similar procedure as described forExample 97 with 3-bromo-2-methylaniline replacing3-bromo-2-chloroaniline in step 2. The enantiopure compounds wereobtained by chiral HPLC separation. The enantiopure compound (Peak 2compound) that was eluted second in the chromatography was used for nextreactions. LC-MS calculated for C₂₄H₂₈BrN₄O₂ (M+H)⁺: m/z=483.1, 485.1;found 483.1, 485.1.

Step 2:(3R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(3-(pyrrolidin-2-yl)-1,7-naphthyridin-8-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 97 with tert-butyl2-(8-(3-bromo-2-methylphenylamino)-1,7-naphthyridin-3-yl)pyrrolidine-1-carboxylatereplacing tert-butyl2-(8-(3-bromo-2-chlorophenylamino)-1,7-naphthyridin-3-yl)pyrrolidine-1-carboxylatein Step 3. The reaction mixture was diluted with MeOH and then purifiedby prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired productas TFA salt. LC-MS calculated for C₄₀H₃₈N₇O₃ (M+H)⁺: m/z=664.3; found664.3.

Example 100(R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 24 with (R)-3-methylpyrrolidine-3-carboxylic acid replacing(R)-pyrrolidine-3-carboxylic acid in Step 5. The reaction mixture wasdiluted with MeOH and then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₄₂H₄₂N₇O₄ (M+H)⁺: m/z=708.3; found 708.3. ¹H NMR (500MHz, DMSO) δ 9.07 (s, 1H), 8.52 (s, 1H), 8.41 (s, 1H), 8.21 (m, 2H),8.15 (s, 1H), 8.06 (s, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.49 (d, J=7.5 Hz,1H), 7.42 (t, J=7.7 Hz, 1H), 7.24 (d, J=5.8 Hz, 1H), 7.05 (d, J=6.3 Hz,1H), 4.85-4.41 (m, 5H), 3.96-3.21 (m, 8H), 2.50 (s, 3H), 2.37 (m, 2H),2.08 (s, 3H), 1.87 (m, 2H), 1.38 (s, 3H).

Example 101(R)-3-((7-cyano-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methylamino)propanoicAcid

This compound was prepared using similar procedures as described forExample 24 with 3-aminopropanoic acid replacing(R)-pyrrolidine-3-carboxylic acid in Step 5. The reaction mixture wasdiluted with MeOH and then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₃₉H₃₈N₇O₄ (M+H)⁺: m/z=668.3; found 668.3.

Example 102(R)-1-((7-cyano-2-(3′-(3-fluoro-4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: (R)-1-((2-bromo-3-fluoropyridin-4-yl)methyl)pyrrolidin-3-ol

A mixture of 2-bromo-3-fluoroisonicotinaldehyde (70.0 mg, 0.343 mmol)and (R)-pyrrolidin-3-ol (59.8 mg, 0.686 mmol) in DCM (2.0 ml) wasstirred at r.t. for 10 min. Sodium triacetoxyborohydride (218 mg, 1.029mmol) was then added and the mixture was stirred at r.t. for 2 h. Themixture was diluted with DCM, washed with 1 N NaOH, water, brine, driedover Na₂SO₄, filtered and concentrated. The product was purified bychromatography eluting with DCM/MeOH (MeOH 0-10%). LC-MS calculated forC₁₀H₁₃BrFN₂O (M+H)⁺: m/z=275.0, 277.0; found 275.1, 277.1.

Step 2:(R)-1-((3-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamino)pyridin-4-yl)methyl)pyrrolidin-3-ol

A mixture of2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.254g, 1.090 mmol),(R)-1-((2-bromo-3-fluoropyridin-4-yl)methyl)pyrrolidin-3-ol (0.20 g,0.727 mmol), cesium carbonate (0.592 g, 1.817 mmol) andchloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.019 g, 0.022 mmol) in dioxane (3.0 ml) was vacuumed and refilled withnitrogen and then stirred at 100° C. for 2 h. The mixture was filteredand concentrated and the crude was used in the next step directly. LC-MScalculated for C₂₃H₃₂BFN₃O₃ (M+H)⁺: m/z=428.2; found 428.3.

Step 3:(R)-7-chloro-2-(3′-((3-fluoro-4-((3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-5-carbaldehyde

A mixture of(R)-1-((3-fluoro-2-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)pyridin-4-yl)methyl)pyrrolidin-3-ol(0.10 g, 0.234 mmol),2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazole-5-carbaldehyde(Example 10, Step 1: 0.098 g, 0.281 mmol), potassium phosphate, tribasic(0.099 g, 0.468 mmol) and tetrakis(triphenylphosphine)palladium(0)(0.027 g, 0.023 mmol) in dioxane (2 ml) and water (0.5 ml) was vacuumedand refilled with nitrogen for 3 times and then the reaction was stirredat 110° C. for 3 h. The mixture was diluted with water and ethylacetate, the organic phase was separated and washed with water, brinedried and concentrated. The product was purified by chromatographeluting with DCM/MeOH (MeOH 0-15%). LC-MS calculated for C₃₂H₂₉ClFN₄O₃(M+H)⁺: m/z=571.2; found 571.1.

Step 4:(R)-2-(3′-(3-fluoro-4-((3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-ylamino)-2,2′-dimethylbiphenyl-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile

This compound was prepared using similar procedures as described forExample 12 with(R)-7-chloro-2-(3′-((3-fluoro-4-((3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-5-carbaldehydereplacing(7-chloro-2-(2,2′-dimethyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)benzol[d]oxazol-5-yl)methanolin Step 1. LC-MS calculated for C₃₃H₂₉FN₅O₃ (M+H)⁺: m/z=562.2; found562.3.

Step 5:(R)-1-((7-cyano-2-(3′-(3-fluoro-4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 16 with(R)-2-(3′-(3-fluoro-4-((3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-ylamino)-2,2′-dimethylbiphenyl-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrilereplacing(S)-7-chloro-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazole-5-carbaldehydein Step 7. The reaction mixture was diluted with MeOH and then purifiedby prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired productas TFA salt. LC-MS calculated for C₃₈H₃₈FN₆O₄ (M+H)⁺: m/z=661.3; found661.4.

Example 103(R)-1-((2-(2′-chloro-3′-(6-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-N-methylpyrrolidine-3-carboxamide

Hunig's base (8.2 μl, 0.047 mmol) was added to a DMF (157 μl) solutionof(R)-1-((2-(2′-chloro-3′-(6-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (Example 87, 20 mg, 0.031 mmol), 2M methylamine in THF (23.6 μl,0.047 mmol), and (benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate (16.7 mg, 0.038 mmol). After stirring at roomtemperature for 1 h, the mixture was concentrated and diluted with MeOHand then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to givethe desired product as its TFA salt. LC-MS calculated for C₃₇H₃₉ClN₇O₂(M+H)⁺: m/z=648.3; found 648.3.

Example 104(R)-1-((2-(2′-chloro-3′-(6-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-N-(2-hydroxyethyl)pyrrolidine-3-carboxamide

Hunig's base (8.2 μl, 0.047 mmol) was added to a DMF (157 μl) solutionof(R)-1-((2-(2′-chloro-3′-(6-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (Example 87, 20 mg, 0.031 mmol), 2-aminoethanol (4.0 μl, 0.047mmol), and (benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate (16.7 mg, 0.038 mmol). After stirring at roomtemperature for 1 h, the mixture was concentrated and diluted with MeOHand then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to givethe desired product as its TFA salt. LC-MS calculated for C₃₈H₄₁ClN₇O₃(M+H)⁺: m/z=678.3; found 678.3.

Example 105(R)-1-((7-cyano-2-(3′-(5-(2-(dimethylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: tert-butyl 2-bromo-4H-pyrrolo[3,4-d]thiazole-5(6H)-carboxylate

To a stirred solution of 2-bromo-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole,HBr (Aurum Pharm, cat #MR22320: 220.0 mg, 0.769 mmol) andN,N-diisopropylethylamine (0.269 ml, 1.539 mmol) in DCM (5.0 ml),Boc-anhydride (201 mg, 0.923 mmol) was added at room temperature. After1 hour, the reaction mixture was diluted with EtOAc (100 mL), and washedwith water (3×15 mL). The organic layer was dried over Na₂SO₄, filteredand the filtrate was concentrated to afford crude tert-butyl2-bromo-4H-pyrrolo[3,4-d]thiazole-5(6H)-carboxylate (220 mg, 0.724 mmol,93.6% yield), which was used directly in the next step without furtherpurification. LC-MS calculated for C₁₀H₁₄BrN₂O₂S (M+H)⁺:m/z=305.0/307.0; found 305.0/307.0.

Step 2: tert-butyl2-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-4H-pyrrolo[3,4-d]thiazole-5(6H)-carboxylate

A slurry of(7-chloro-2-(2,2′-dimethyl-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanol(Example 59, Step 2: 275 mg, 0.561 mmol), tert-butyl2-bromo-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate (171 mg,0.561 mmol), tetrakis(triphenylphosphine)palladium(0) (64.9 mg, 0.056mmol) and sodium carbonate (149 mg, 1.404 mmol) in 1,4-dioxane (6 mL)and water (2 mL) was stirred at 100° C. overnight. After cooled to roomtemperature, the reaction mixture was diluted with EtOAc (150 mL), andwashed with water (3×15 mL). The organic layer was dried over Na₂SO₄,filtered and the filtrate was concentrated. The crude product waspurified on a silica gel column, eluting with 0-40% EtOAc/DCM to affordtert-butyl2-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-4H-pyrrolo[3,4-d]thiazole-5(6H)-carboxylate(280 mg, 0.476 mmol, 85% yield). LC-MS calculated for C₃₂H₃₁ClN₃O₄S(M+H)⁺: m/z=588.2; found 588.3.

Step 3: tert-butyl2-(3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-4H-pyrrolo[3,4-d]thiazole-5(6H)-carboxylate

This compound was prepared using similar procedures as described forExample 12 with tert-butyl2-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylatereplacing(7-chloro-2-(2,2′-dimethyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanolin Step 1. LC-MS calculated for C₃₃H₃₁N₄O₄S (M+H)⁺: m/z=579.2; found579.2.

Step 4: tert-butyl2-(3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-4H-pyrrolo[3,4-d]thiazole-5(6H)-carboxylate

To a stirred solution of tert-butyl2-(3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate(0.93 g, 1.607 mmol) in DCM (10.0 mL), dess-martin periodinane (1.022 g,2.411 mmol) was added at room temperature. After 1 hour, the reactionmixture was quenched with saturated aq. NaHCO₃, and extracted with DCM(4×80 mL). The organic layers were combined, dried over Na₂SO₄, filteredand the filtrate was concentrated under reduced pressure to afford crudetert-butyl2-(3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-4H-pyrrolo[3,4-d]thiazole-5(6H)-carboxylate(0.90 g, 1.56 mmol, 97% yield), which was used directly in the next stepwithout further purification. LC-MS calculated for C₃₃H₂₉N₄O₄S (M+H)⁺:m/z=577.2; found 577.1.

Step 5:2-(3′-(5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile

tert-butyl2-(3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-4H-pyrrolo[3,4-d]thiazole-5(6H)-carboxylate(200 mg, 0.347 mmol) was dissolved in DCM (1 mL) and TFA (1 mL). Theresulted solution was stirred at room temperature for 1 hour. Thevolatiles were then removed under reduced pressure to afford2-(3′-(5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrileas its TFA salt, which was used directly in the next step withoutfurther purification. LC-MS calculated for C₂₈H₂₁N₄O₂S (M+H)⁺:m/z=477.1; found 477.1.

Step 6:2-(3′-(5-(2-(dimethylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile

To a stirred solution of2-(3′-(5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile(100.0 mg, 0.210 mmol) and dimethylglycine (26.0 mg, 0.250 mmol) in DMF(5.0 ml), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (79.8 mg, 0.210 mmol), and N,N-diisopropylethylamine(146.2 μl, 0.84 mmol) were added sequentially at room temperature. After1 hour, the reaction was diluted with EtOAc (100 mL) and washed withwater (3×10 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated to afford crude2-(3′-(5-(2-(dimethylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile(105 mg, 0.187 mmol, 89% yield). LC-MS calculated for C₃₂H₂₈N₅O₃S(M+H)⁺: m/z=562.2; found 562.2.

Step 7:(R)-1-((7-cyano-2-(3′-(5-(2-(dimethylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A solution of (R)-pyrrolidine-3-carboxylic acid (15.37 mg, 0.134 mmol),2-(3′-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile(50.0 mg, 0.089 mmol) and N,N-diisopropylethylamine (0.019 mL, 0.107mmol) in CH₂Cl₂ (5.0 mL) was allowed to stir for 1 hour. Then sodiumtriacetoxyborohydride (56.6 mg, 0.267 mmol) was added. The resultedmixture was stirred at room temperature overnight. The volatiles wereremoved under reduced pressure and the residue was purified by prep LCMS(pH 2, acetonitrile/water+TFA) to give the desired product as its TFAsalt. LC-MS calculated for C₃₇H₃₇N₆O₄S (M+H)⁺: m/z=661.3; found 661.2.¹H NMR (600 MHz, DMSO) δ 8.38 (s, 1H), 8.20 (dd, J=7.9, 1.2 Hz, 1H),8.12 (s, 1H), 7.75-7.70 (m, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.50-7.45 (m,2H), 7.33 (d, J=6.4 Hz, 1H), 4.99-4.64 (m, 4H), 4.56 (br, s, 2H), 4.29(d, J=12.3 Hz, 2H), 3.72-3.16 (m, 5H), 2.87 (s, 3H), 2.86 (s, 3H), 2.44(s, 3H), 2.20 (d, J=5.3 Hz, 3H), 2.25-1.99 (m, 2H).

Example 106(R)-1-((7-cyano-2-(3′-(5-(3-(dimethylamino)propanoyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 105 with 3-(dimethylamino)propanoic acid replacingdimethylglycine in Step 6. The crude product was purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired compound as its TFAsalt. LC-MS calculated for C₃₈H₃₉N₆O₄S (M+H)⁺: m/z=675.3; found 675.3.

Example 107(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(5-((S)-1-methylpyrrolidine-2-carbonyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 105 with (S)-1-methylpyrrolidine-2-carboxylic acid replacingdimethylglycine in Step 6. The crude product was purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired compound as its TFAsalt. LC-MS calculated for C₃₉H₃₉N₆O₄S (M+H)⁺: m/z=687.3; found 687.2.

Example 108(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(5-(2-(4-methylpiperazin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 105 with 2-(4-methylpiperazin-1-yl)acetic acid replacingdimethylglycine in Step 6. The crude product was purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired compound as its TFAsalt. LC-MS calculated for C₄₀H₄₂N₇O₄S (M+H)⁺: m/z=716.3; found 716.2.

Example 109(R)-1-((7-cyano-2-(3′-(5-(2-(dimethylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 105 with (R)-3-methylpyrrolidine-3-carboxylic acid replacing(R)-pyrrolidine-3-carboxylic acid in Step 7. The crude product waspurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredcompound as its TFA salt. LC-MS calculated for C₃₈H₃₉N₆O₄S (M+H)⁺:m/z=675.3; found 675.3.

Example 110(R)-1-((7-cyano-2-(3′-(5-(2-(isopropylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:(R)-1-((2-(3′-(5-(tert-butoxycarbonyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A slurry of (R)-pyrrolidine-3-carboxylic acid (39.9 mg, 0.347 mmol),tert-butyl2-(3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate(Example 105, Step 4: 100.0 mg, 0.173 mmol) andN,N-diisopropylethylamine (0.045 mL, 0.260 mmol) in CH₂Cl₂ (5.0 mL) wasallowed to stir for 1 hour at room temperature. Then sodiumtriacetoxyborohydride (110 mg, 0.520 mmol) was added. The resultedmixture was stirred at room temperature overnight. Then the mixture wasdiluted with DCM (100 mL) and washed with water (3×15 mL). The aqueouslayers were combined and extracted with DCM/iPrOH (2:1, 3×30 mL). Theorganic layers were combined, dried over Na₂SO₄, filtered and thefiltrate was concentrated to afford crude product, which was used in thenext step without further purification. LC-MS calculated for C₃₈H₃₈N₅O₅S(M+H)⁺: m/z=676.3; found 676.2.

Step 2:(R)-1-((7-cyano-2-(3′-(5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

(R)-1-((2-(3′-(5-(tert-butoxycarbonyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (105 mg, 0.155 mmol) was dissolved in DCM/TFA (1:1, 2.0 mL). Theresulted solution was stirred at room temperature for 1 hour. Thevolatiles were removed under reduced pressure to afford the desiredproduct as its TFA salt, which was used directly in the next stepwithout further purification. LC-MS calculated for C₃₃H₃₀N₅O₃S (M+H)⁺:m/z=576.2; found 576.2.

Step 3:(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(5-(2-oxoacetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a stirred solution of(R)-1-((7-cyano-2-(3′-(5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (700.0 mg, 1.216 mmol) and 2-oxoacetic acid (270 mg, 3.65 mmol) inDMF (8.0 ml), N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (462 mg, 1.216 mmol), and N,N-diisopropylethylamine(0.424 ml, 2.432 mmol) were added sequentially at rt. After 1 h, themixture was diluted with EtOAc (200 mL) and washed with water (3×25 mL).The aqueous layers were combined and extracted with DCM/iPrOH (2:1, 3×50mL). The organic layers were combined, dried over Na₂SO₄, filtered andthe filtrate was concentrated to afford the desired aldehyde (710 mg,1.12 mmol, 92.3% yield). LC-MS calculated for C₃₅H₃₀N₅O₅S (M+H)⁺:m/z=632.2; found 632.2.

Step 4:(R)-1-((7-cyano-2-(3′-(5-(2-(isopropylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A slurry of propan-2-amine (5.61 mg, 0.095 mmol) and(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(5-(2-oxoacetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (30.0 mg, 0.047 mmol), N,N-diisopropylethylamine (0.025 ml, 0.142mmol) in DMF (3.0 ml) was allowed to stir for 1 h at room temperature.Sodium cyanoborohydride (8.95 mg, 0.142 mmol) was then added. Theresulted mixture was stirred at room temperature overnight. The reactionmixture was then diluted with MeOH and was purified on prep-LCMS (pH 2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₃₈H₃₉N₆O₄S (M+H)⁺: m/z=675.3; found 675.2. ¹H NMR(500 MHz, DMSO) δ 8.85 (s, 1H), 8.40 (s, 1H), 8.22 (d, J=6.8 Hz, 1H),8.14 (s, 1H), 7.74 (d, J=7.7 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.49 (t,J=6.9 Hz, 2H), 7.35 (d, J=7.5 Hz, 1H), 5.09-4.66 (m, 4H), 4.57 (s, 2H),4.09 (m, 2H), 3.70-3.15 (m, 6H), 2.46 (s, 3H), 2.23 (m, 1H), 2.22 (d,J=5.3 Hz, 3H), 2.07 (m, 1H), 1.28 (d, J=6.5 Hz, 6H).

Example 111(R)-1-((7-cyano-2-(3′-(5-(2-((R)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 110 with (R)-pyrrolidin-3-ol replacing propan-2-amine in Step 4.The crude product was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired compound as its TFA salt.LC-MS calculated for C₃₉H₃₉N₆O₅S (M+H)⁺: m/z=703.3; found 703.2.

Example 112(R)-1-((7-cyano-2-(3′-(5-(2-((S)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 110 with (S)-pyrrolidin-3-ol replacing propan-2-amine in Step 4.The crude product was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired compound as its TFA salt.LC-MS calculated for C₃₉H₃₉N₆O₅S (M+H)⁺: m/z=703.3; found 703.2.

Example 113(R)-1-((2-(3′-(5-(2-(azetidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 110 with azetidin replacing propan-2-amine in Step 4. The crudeproduct was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to givethe desired compound as its TFA salt. LC-MS calculated for C₃₈H₃₇N₆O₄S(M+H)⁺: m/z=673.3; found 673.2.

Example 114(R)-1-((7-cyano-2-(3′-(5-(2-(ethyl(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 110 with N-methylethanamine replacing propan-2-amine in Step 4.The crude product was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired compound as its TFA salt.LC-MS calculated for C₃₈H₃₉N₆O₄S (M+H)⁺: m/z=675.3; found 675.3.

Example 115(R)-1-((7-cyano-2-(3′-(5-(2-((S)-3-hydroxy-3-methylpyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 110 with (S)-3-methylpyrrolidin-3-ol replacing propan-2-amine inStep 4. The crude product was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired compound as its TFA salt.LC-MS calculated for C₄₀H₄₁N₆O₅S (M+H)⁺: m/z=717.3; found 717.2.

Example 116(R)-1-((7-cyano-2-(3′-(5-(2-((R)-3-hydroxy-3-methylpyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 110 with (R)-3-methylpyrrolidin-3-ol replacing propan-2-amine inStep 4. The crude product was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired compound as its TFA salt.LC-MS calculated for C₄₀H₄₁N₆O₅S (M+H)⁺: m/z=717.3; found 717.3.

Example 117(R)-1-((7-cyano-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-N-methylpyrrolidine-3-carboxamide

In a 1 dram vial(R)-1-((7-cyano-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (Example 63, final product: 20 mg, 0.032 mmol) and methylamine inTHF (2.0 M, 100 uL) were dissolved in DMF. DIPEA (27.6 μl, 0.158 mmol)andN-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (36.1 mg, 0.095 mmol) were added to thereaction mixture in one portion. After 5 h, the reaction mixture wasdiluted with MeOH then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₃₈H₄₁N₆O₂S (M+H)⁺: m/z=645.3; found 645.2.

Example 118N-(2-(((7-cyano-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)amino)ethyl)acetamide

Step 1:2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrile

In a 4 dram vial tert-butyl2-(3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(Example 63, Step 1: 368 mg, 0.62 mmol) in methanol (3 ml) was treatedwith 4 N HCl in 1,4-dioxane (2 mL). The reaction mixture was heated to40° C. After 2 h, the reaction mixture was concentrated to dryness andused as crude without further purification. LC-MS calculated forC₂₉H₂₅N₄O₂S (M+H)⁺: m/z=493.2; found 493.1.

Step 2:5-(hydroxymethyl)-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile

In a 1 dram vial2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrile(306 mg, 0.62 mmol) was dissolved in DCM (3 mL) to give a yellowsolution. Acetone (306 μL, 4.17 mmol) and DIPEA (292 μL, 1.67 mmol) wereadded to the reaction mixture. After 1 h, sodium triacetoxyborohydride(880 mg, 4.17 mmol) was added to the reaction mixture. After 5 h,saturated NaHCO₃ (5 mL) was added followed by extraction with DCM (5mL×4). The combined organic layers were dried Na₂SO₄, filtered andconcentrated. The crude product was used directly in the next step.LC-MS calculated for C₃₂H₃₁N₄O₂S (M+H)⁺: m/z=535.2; found 535.3.

Step 3:5-formyl-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile

To a solution of5-(hydroxymethyl)-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile(332 mg, 0.62 mmol) in DCM (4 mL) was added Dess-Martin periodinane (395mg, 0.93 mmol). After 1 h, saturated NaHCO₃ (5 mL) was added to thereaction mixture followed by extraction with DCM (5 mL×3). The combinedorganic layers were dried Na₂SO₄, filtered and concentrated. The crudeproduct was used for next step without further purification. LC-MScalculated for C₃₂H₂₉N₄O₂S (M+H)⁺: m/z=533.2; found 533.3.

Step 4:N-(2-(((7-cyano-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)amino)ethyl)acetamide

In a 1 dram vial5-formyl-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile(10 mg, 0.019 mmol), DIPEA (5 μL, 0.032 mmol) andN-acetylethylenediamine (Aldrich, cat #397261: 5 mg) were dissolved inDMF (0.5 mL). The reaction mixture was stirred at r.t. for 12 h, andthen sodium cyanoborohydride (6 mg, 0.095 mmol) was added to thereaction mixture in one portion. After 2 h, the reaction mixture wasdiluted with MeOH then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₃₆H₃₉N₆O₂S (M+H)⁺: m/z=619.3; found 619.2.

Example 119(R)-1-((7-cyano-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-N-(2-hydroxyethyl)pyrrolidine-3-carboxamide

This compound was prepared using similar procedures as described forExample 117 with ethanolamine replacing methylamine. The reactionmixture was diluted with MeOH then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₃₉H₄₃N₆O₃S (M+H)⁺: m/z=675.3; found 675.3.

Example 1205-(((2-hydroxyethyl)amino)methyl)-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile

This compound was prepared using similar procedures as described forExample 118 with ethanolamine replacing N-acetylethylenediamine in Step4. The reaction mixture was diluted with MeOH then purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₃₄H₃₆N₅O₂S (M+H)⁺: m/z=578.3; found 578.2.

Example 121(R)-5-((3-hydroxypyrrolidin-1-yl)methyl)-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile

This compound was prepared using similar procedures as described forExample 118 with (R)-3-Hydroxypyrrolidine (Aldrich, cat #382981)replacing N-acetylethylenediamine in Step 4. The reaction mixture wasdiluted with MeOH then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₃₆H₃₈N₅O₂S (M+H)⁺: m/z=604.3; found 604.2.

Example 122(R)-1-((7-cyano-2-(3′-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: Benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (Aldrich,cat #494127: 12.4 g, 61.0 mmol) in DCM (200 ml) was addedmeta-chloroperoxybenzoic acid (16.20 g, 61.0 mmol). The resultingmixture was stirred at room temperature for 3 h. The reaction wasquenched with saturated. NaHCO₃ solution, the organic layer wasseparated; the aqueous layer was extracted with DCM once. The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated. Thecrude was purified with flash chromatography (eluting with 0-50% ethylacetate in hexanes) to give the desired product as clear oil (13 g,97%). LC-MS calculated for C₁₂H₁₄NO₃ (M+H)⁺: m/z=220.1; found 220.1.

Step 2: Benzyl 3-amino-4-hydroxypyrrolidine-1-carboxylate

To a flask was charged with benzyl6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (13.0 g, 59.3 mmol) andammonium hydroxide (115 ml, 2.96 mol). The reaction mixture was heatedat 90° C. overnight. The solvent was removed. The residue was used inthe next step without purification. LC-MS calculated for C₁₂H₁₇N₂O₃(M+H)⁺: m/z=237.1; found 237.1.

Step 3: Benzyl3-(3-bromo-2-methylbenzamido)-4-hydroxypyrrolidine-1-carboxylate

A solution of 3-bromo-2-methylbenzoic acid (9.70 g, 45.1 mmol) in DMF(226 ml) was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (18.87 g, 49.6 mmol). After stirring for 5 min,benzyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (10.66 g, 45.1 mmol)and N,N-diisopropylethylamine (23.57 ml, 135 mmol) was added. Thereaction mixture was stirred at room temperature for 2 h. The reactionwas diluted with water, the aqueous layer was extracted with DCM once.The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified with flash chromatography(eluting with 0-60% ethyl acetate in hexanes) to give the desiredproduct (11.5 g, 59%). LC-MS calculated for C₂₀H₂₂BrN₂O₄ (M+H)⁺:m/z=433.1; found 433.1.

Step 4. benzyl3-(3-bromo-2-methylbenzamido)-4-oxopyrrolidine-1-carboxylate

To a solution of benzyl3-(3-bromo-2-methylbenzamido)-4-hydroxypyrrolidine-1-carboxylate (16.50g, 38.1 mmol) in DCM (200 ml) was added Dess-Martin periodinane (19.38g, 45.7 mmol). The resulting mixture was stirred at room temperature for2 h. The reaction mixture was diluted with Et₂O and 1 M NaOH solution.After stirring for 1 h, the organic layer was separated and dried overNa₂SO₄, filtered and concentrated. The residue was purified with flashchromatography (eluting with 0-50% ethyl acetate in hexanes) to give thedesired product (9.2 g, 56%). LC-MS calculated for C₂₀H₂₀BrN₂O₄ (M+H)⁺:m/z=431.1; found 431.1.

Step 5: benzyl2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazole-5-carboxylate

To a solution of benzyl3-(3-bromo-2-methylbenzamido)-4-oxopyrrolidine-1-carboxylate (9.23 g,21.40 mmol) in 1,4-dioxane (100 ml) was added POCl₃ (2.00 ml, 21.40mmol). The resulting mixture was stirred at 110° C. for 3 h. Aftercooling to room temperature, the reaction mixture was diluted withsaturated NaHCO₃ solution and ethyl acetate. The aqueous layer wasextracted with ethyl acetate once. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Theprecipitate was collected via filtration and washed with ethyl acetateand hexanes to give the desired product as off white solid (4.85 g,55%). LC-MS calculated for C₂₀H₁₈BrN₂O₃ (M+H)⁺: m/z=413.0; found 413.0.

Step 6. 2-(3-Bromo-2-methylphenyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazole

To solution of benzyl2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazole-5-carboxylate(3.70 g, 8.95 mmol) in DCM (60 ml) was added 1 M BBr₃ in DCM solution(17.91 ml, 17.91 mmol) at 0° C. After stirring at same temperature for 1h, the reaction mixture was diluted DCM and saturated NaHCO₃ solution.The resultant precipitate was collected vial filtration and dried undervacuum to give the desired product as white solid (2.0 g, 80%). LC-MScalculated for C₁₂H₁₂BrN₂O (M+H)⁺: m/z=279.0; found 279.0.

Step 7.1-(2-(3-Bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(dimethylamino)ethan-1-one

A solution of dimethylglycine (20.5 mg, 0.199 mmol) inN,N-dimethylformamide (1 ml) was addedN,N,N′N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (104 mg, 0.274 mmol). After stirring for 5 min,2-(3-bromo-2-methylphenyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazole (55.5mg, 0.199 mmol) and N,N-diisopropylethylamine (104 μl, 0.596 mmol). Thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was diluted with water, the aqueous layer was extracted with DCMonce. The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified with silica gel column (elutingwith 0-30% MeOH in DCM) to give the desired product (35 mg, 49%). LC-MScalculated for C₁₆H₁₉BrN₃O₂ (M+H)⁺: m/z=364.1; found 364.1.

Step 8:2-(3′-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrile

A mixture of1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(dimethylamino)ethan-1-one(35.0 mg, 0.096 mmol),5-(hydroxymethyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile(Example 54, Step 2: 37.5 mg, 0.096 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (7.56 mg, 9.61 μmol) and tripotassium phosphate hydrate (48.7 mg,0.211 mmol) in 1,4-dioxane (1.5 mL)/water (0.5 mL) was stirred at 80° C.under N₂ atmosphere for 1 h. The mixture was diluted with methanol and 1N HCl solution and purified with prep-LCMS (pH 2) to give the desiredproduct as light yellow solid (28 mg, 53%). LC-MS calculated forC₃₂H₃₀N₅O₄ (M+H)⁺: m/z=548.2; found 548.3.

Step 9:2-(3′-(5-(Dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile

To a solution of2-(3′-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrile(28 mg, 0.051 mmol) in DCM (2 ml) was added Dess-Martin periodinane(26.0 mg, 0.061 mmol). The resulting mixture was stirred at roomtemperature for 2 h. The reaction mixture was diluted with Et₂O and 1 MNaOH solution. After stirring for 1 h, the organic layer was separatedand dried over Na₂SO₄, filtered and concentrated to give the desiredproduct (28 mg, 100%). LC-MS calculated for C₃₂H₂₈N₅O₄ (M+H)⁺:m/z=546.2; found 546.3.

Step 10:(R)-1-((7-Cyano-2-(3′-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of(2-(3′-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile(10.0 mg, 0.018 mmol), (R)-pyrrolidine-3-carboxylic acid (2.1 mg, 0.018mmol) in DCM (0.5 ml) was added DIEA (3.20 μl, 0.018 mmol). Afterstirring at room temperature for 2.5 h, sodium triacetoxyborohydride(7.77 mg, 0.037 mmol) was added and stirred overnight. Solvent wasremoved in vacuo. The residue was dissolved in methanol and water andpurified with prep LCMS (pH 2, acetonitrile/water+TFA) to give thedesired product as TFA salt. LC-MS calculated for C₃₇H₃₇N₆O₅ (M+H)⁺:m/z=645.3; found 645.3. ¹H NMR (600 MHz, DMSO) δ 8.39 (s, 1H), 8.22 (m,1H), 8.13 (s, 1H), 8.00 (m, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.55-7.46 (m,2H), 7.37 (d, J=7.5 Hz, 1H), 4.84 (d, J=2.7 Hz, 1H), 4.73 (d, J=2.7 Hz,1H), 4.65 (t, J=2.8 Hz, 1H), 4.55 (m, 3H), 4.30 (d, J=11.9 Hz, 2H),3.70-3.10 (m, 5H), 2.89 (s, 6H), 2.44 (s, 3H), 2.35 (m, 5H).

Example 1231-((7-cyano-2-(3′-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 122 with azetidine-3-carboxylic acid replacing(R)-pyrrolidine-3-carboxylic acid in Step 10. The reaction mixture waspurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as TFA salt. LC-MS calculated for C₃₆H₃₅N₆O₅ (M+H)⁺: m/z=631.3;found 631.3.

Example 124(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(5-(methyl-L-prolyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:2-(3-bromo-2-methylphenyl)-5-(methyl-L-prolyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazole

This compound was prepared using similar procedures as described forExample 122 with methyl-L-proline replacing dimethylglycine in Step 7.LC-MS calculated for C₁₈H₂₁BrN₃O₂ (M+H)⁺: m/z=390.1, 392.1; found 390.1,392.1.

Step 2:2-(2,2′-dimethyl-3′-(5-(methyl-L-prolyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-[1,1′-biphenyl]-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrile

This compound was prepared using similar procedures as described forExample 122 with2-(3-bromo-2-methylphenyl)-5-(methyl-L-prolyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazolereplacing1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(dimethylamino)ethan-1-onein Step 8 LC-MS calculated for C₃₄H₃₂N₅O₄ (M+H)⁺: m/z=574.2; found574.2.

Step 3:2-(2,2′-dimethyl-3′-(5-(methyl-L-prolyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-[1,1′-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile

This compound was prepared using similar procedures as described forExample 122 with2-(2,2′-dimethyl-3′-(5-(methyl-L-prolyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-[1,1′-biphenyl]-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrilereplacing2-(3′-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrilein Step 9. LC-MS calculated for C₃₄H₃₀N₅O₄ (M+H)⁺: m/z=572.2; found572.2.

Step 4:(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(5-(methyl-L-prolyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 122 with(2-(2,2′-dimethyl-3′-(5-(methyl-L-prolyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-[1,1′-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrilereplacing(2-(3′-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrilein Step 10. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₃₉H₃₉N₆O₅ (M+H)⁺: m/z=671.3; found 671.3.

Example 125(R)-1-((7-cyano-2-(3′-(5-(3-(dimethylamino)propanoyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-3-(dimethylamino)propan-1-one

This compound was prepared using similar procedures as described forExample 122 with 3-(dimethylamino)propanoic acid hydrochloride replacingdimethylglycine in Step 7. LC-MS calculated for C₁₇H₂₁BrN₃O₂ (M+H)⁺:m/z=378.1, 380.1; found 378.1, 380.1.

Step 2:2-(3′-(5-(3-(dimethylamino)propanoyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrile

This compound was prepared using similar procedures as described forExample 122 with1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-3-(dimethylamino)propan-1-onereplacing1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(dimethylamino)ethan-1-onein Step 8. LC-MS calculated for C₃₃H₃₂N₅O₄ (M+H)⁺: m/z=562.2; found562.2.

Step 3:2-(3′-(5-(3-(dimethylamino)propanoyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile

This compound was prepared using similar procedures as described forExample 122 with2-(3′-(5-(3-(dimethylamino)propanoyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrilereplacing2-(3′-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrilein Step 9. LC-MS calculated for C₃₃H₃₀N₅O₄ (M+H)⁺: m/z=560.2; found560.2.

Step 4:(R)-1-((7-cyano-2-(3′-(5-(3-(dimethylamino)propanoyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 122 with2-(3′-(5-(3-(dimethylamino)propanoyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrilereplacing(2-(3′-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrilein Step 10. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₃₈H₃₉N₆O₅ (M+H)⁺: m/z=659.3; found 659.3.

Example 126(R)-1-((7-cyano-2-(3′-(5-(2-((R)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-chloroethan-1-one

A solution of2-(3-bromo-2-methylphenyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazole (1.04 g,3.73 mmol) in CH₂Cl₂ (18 ml) was added 2-chloroacetyl chloride (0.421 g,3.73 mmol) and N,N-diisopropylethylamine (1.947 ml, 11.18 mmol) at 0° C.The reaction mixture was stirred at room temperature for 2 h. Thereaction was diluted with water, and the aqueous layer was extractedwith DCM once. The combined organic layers were dried over Na₂SO₄,filtered and concentrated. The residue was purified with flashchromatography (eluting with 0-60% ethyl acetate in hexanes) to give thedesired product as white solid (0.65 g, 49%). LC-MS calculated forC₁₄H₁₃BrClN₂O₂ (M+H)⁺: m/z=355.0, 357.0; found 355.0, 357.0.

Step 2:(R)-1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(3-hydroxypyrrolidin-1-yl)ethan-1-one

The mixture of1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-chloroethan-1-one(12 mg, 0.034 mmol), (R)-pyrrolidin-3-ol (2.94 mg, 0.034 mmol),potassium carbonate (4.66 mg, 0.034 mmol) and DMF (1.0 ml) was heated at100° C. for 2 h. The reaction mixture was diluted with methanol and 1 NHCl, purified with prep LCMS (pH 2) to give the desired product (10 mg,73%). LC-MS calculated for C₁₈H₂₁BrN₃O₃ (M+H)⁺: m/z=406.1, 408.1; found406.1, 408.1.

Step 3:(R)-1-((2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of(2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazole-5-carbaldehyde(Example 10, Step 1: 3.38 g, 9.64 mmol), (R)-pyrrolidine-3-carboxylicacid hydrochloride (1.461 g, 9.64 mmol) in CH₂Cl₂ (150 ml) was addedDIEA (3.87 ml, 22.17 mmol). After stirring at room temperature for 6.5h, sodium triacetoxyborohydride (4.09 g, 19.28 mmol) was added andstirred overnight. Water was added and the mixture was stirredovernight. The precipitate was collected via filtration and washed withwater and ethyl acetate. The organic layer was concentrated and purifiedwith silica gel column (0-100% ethyl acetate in hexanes, then 0-35%methanol in DCM). LC-MS calculated for C₂₀H₁₉BrClN₂O₃ (M+H)⁺: m/z=449.0,451.0; found 449.0, 451.0.

Step 4:(R)-1-((7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A microwave vial charged with(R)-1-((2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (1.20 g, 2.67 mmol), bis(pinacolato)diboron (0.813 g, 3.20 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium (II)dichloromethane adduct (0.218 g, 0.267 mmol) and acetic acid, potassiumsalt, anhydrous (0.655 g, 6.67 mmol) was evacuated under vacuum andrefilled with nitrogen and stirred at 95° C. for 2 h. The crude wasdiluted with DCM, and then filtered through a pad of Celite. Thefiltrate was concentrated. The residue was purified with flashchromatography (0-100% ethyl acetate in hexanes, then 0-35% methanol inDCM). LC-MS calculated for C₂₆H₃₁BClN₂O₅ (M+H)⁺: m/z=497.2; found 497.1.

Step 5:(R)-1-((7-cyano-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

In a microwave vial was combined(R)-1-((7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (1.25 g, 2.52 mmol), potassium ferrocyanide(II) hydrate (0.689 ml,3.02 mmol),[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (0.200 g, 0.252 mmol), potassium acetate(0.247 g, 2.52 mmol), 1,4-dioxane (12 ml), and water (12 ml). The vialwas capped and evacuated under vacuum and refilled with nitrogen. Thereaction was heated to 100° C. for 2 hours. After cooling to roomtemperature, the mixture was diluted with MeOH, passed through a syringefilter and purified on prep LCMS (pH2) to give the desired product (0.72g 59%). LC-MS calculated for C₂₇H₃₁BN₃O₅ (M+H)⁺: m/z=488.2; found 488.3.

Step 6:(R)-1-((7-cyano-2-(3′-(5-(2-((R)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of(R)-1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(3-hydroxypyrrolidin-1-yl)ethan-1-one(10 mg, 0.025 mmol),(R)-1-((7-cyano-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (12.00 mg, 0.025 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (1.937 mg, 2.461 μmol) and tripotassium phosphate hydrate (12.47mg, 0.054 mmol) in 1,4-dioxane (0.6 mL) and water (0.2 mL) was stirredat 80° C. under nitrogen atmosphere for 1 h. The residue was dissolvedin methanol and 1 N HCl solution and purified with prep-LCMS (pH 2) togive the desired product as the TFA salt. LC-MS calculated forC₃₉H₃₉N₆O₆ (M+H)⁺: m/z=687.3; found 687.3. ¹H NMR (600 MHz, DMSO) δ 8.40(d, J=1.2 Hz, 1H), 8.22 (m, 1H), 8.14 (d, J=1.4 Hz, 1H), 8.00 (m, 1H),7.65-7.58 (m, 1H), 7.54-7.46 (m, 2H), 7.37 (d, J=7.6 Hz, 1H), 4.83-4.30(m, 9H), 3.85-3.05 (m, 9H), 2.44 (s, 3H), 2.35 (m, 3H), 2.34-1.85 (m,4H).

Example 127(R)-1-((7-cyano-2-(3′-(5-(2-(3-hydroxyazetidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(3-hydroxyazetidin-1-yl)ethan-1-one

This compound was prepared using similar procedures as described forExample 126 with azetidin-3-ol replacing (R)-pyrrolidin-3-ol in Step 2LC-MS calculated for C₁₇H₁₉BrN₃O₃ (M+H)⁺: m/z=392.1, 394.1; found 392.1,394.1.

Step 2:(R)-1-((7-cyano-2-(3′-(5-(2-(3-hydroxyazetidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 126 with1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(3-hydroxyazetidin-1-yl)ethan-1-onereplacing(R)-1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(3-hydroxypyrrolidin-1-yl)ethan-1-onein Step 6. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₃₈H₃₇N₆O₆ (M+H)⁺: m/z=673.3; found 673.3.

Example 128(R)-1-((7-cyano-2-(3′-(5-(2-((S)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:(S)-1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(3-hydroxypyrrolidin-1-yl)ethan-1-one

This compound was prepared using similar procedures as described forExample 126 with (S)-pyrrolidin-3-ol replacing (R)-pyrrolidin-3-ol inStep 2. LC-MS calculated for C₁₈H₂₁BrN₃O₃ (M+H)⁺: m/z=406.1, 408.1;found 406.1, 408.1.

Step 2:(R)-1-((7-cyano-2-(3′-(5-(2-((S)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 126 with(S)-1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(3-hydroxypyrrolidin-1-yl)ethan-1-onereplacing(R)-1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(3-hydroxypyrrolidin-1-yl)ethan-1-onein Step 6. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₃₉H₃₉N₆O₆ (M+H)⁺: m/z=687.3; found 687.3.

Example 129(R)-1-((7-cyano-2-(3′-(5-(2-(3-hydroxy-3-methylazetidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(3-hydroxy-3-methylazetidin-1-yl)ethan-1-one

This compound was prepared using similar procedures as described forExample 126 with 3-methylazetidin-3-ol hydrochloride replacing(R)-pyrrolidin-3-ol in Step 2 LC-MS calculated for C₁₈H₂₁BrN₃O₃ (M+H)⁺:m/z=406.1, 408.1; found 406.1, 408.1.

Step 2:(R)-1-((7-cyano-2-(3′-(5-(2-(3-hydroxy-3-methylazetidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 126 with1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(3-hydroxy-3-methylazetidin-1-yl)ethan-1-onereplacing(R)-1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(3-hydroxypyrrolidin-1-yl)ethan-1-onein Step 6. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₃₉H₃₉N₆O₆ (M+H)⁺: m/z=687.3; found 687.3.

Example 130(R)-1-((2-(3′-(5-(2-(azetidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:2-(azetidin-1-yl)-1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)ethan-1-one

This compound was prepared using similar procedures as described forExample 126 with azetidine replacing (R)-pyrrolidin-3-ol in Step 2.LC-MS calculated for C₁₇H₁₉BrN₃O₂ (M+H)⁺: m/z=376.1, 378.1; found 376.1,378.1.

Step 2:(R)-1-((2-(3′-(5-(2-(azetidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 126 with2-(azetidin-1-yl)-1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)ethan-1-onereplacing(R)-1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(3-hydroxypyrrolidin-1-yl)ethan-1-onein Step 6. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₃₈H₃₇N₆O₅ (M+H)⁺: m/z=657.3; found 657.3.

Example 131(S)-1-(2-(2-(3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)pyrrolidine-3-carboxylicAcid

Step 1:(S)-1-(2-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)pyrrolidine-3-carboxylicAcid

The mixture of1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-chloroethan-1-one(Example 126, Step 1; 15 mg, 0.042 mmol), (S)-pyrrolidine-3-carboxylicacid (4.86 mg, 0.042 mmol), TEA (0.018 ml, 0.127 mmol) andN,N-dimethylformamide (1.0 ml) was heated at 60° C. for 2 h. Thereaction mixture was diluted with methanol and 1 N HCl solution, thenpurified with prep-LCMS (pH 2) to give the desired product (12 mg, 65%).LC-MS calculated for C₁₉H₂₁BrN₃O₄ (M+H)⁺: m/z=434.1, 436.1; found 434.1,436.1.

Step 2:(R)-1-((2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazol-5-yl)methyl)pyrrolidin-3-ol

A mixture of(2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazole-5-carbaldehyde(Example 10, Step 1: 0.50 g, 1.426 mmol), (R)-pyrrolidin-3-ol (0.124 g,1.426 mmol) in CH₂Cl₂ (20 ml) was added DIEA (0.573 ml, 3.28 mmol).After stirring at room temperature for 6.5 h, sodiumtriacetoxyborohydride (0.605 g, 2.85 mmol) was added and stirredovernight. Water was added and The organic layer was separated andconcentrated and purified with flash chromatography (eluting with 0-100%ethyl acetate in hexanes, then 0-35% methanol in DCM) to give thedesired product (0.28 g, 46%). LC-MS calculated for C₁₉H₁₉BrClN₂O₂(M+H)⁺: m/z=421.0, 423.0; found 421.0, 423.0.

Step 3:(R)-1-((7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)pyrrolidin-3-ol

A mixture of(R)-1-((2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazol-5-yl)methyl)pyrrolidin-3-ol(278 mg, 0.659 mmol), bis(pinacolato)diboron (201 mg, 0.791 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (53.8 mg, 0.066 mmol) and acetic acid, potassiumsalt, anhydrous (162 mg, 1.648 mmol) was stirred under nitrogenatmosphere at 95° C. for 2 h. The crude was diluted with DCM, and thenfiltered through a pad of Celite. The filtrate was concentrated. Theresidue was purified with flash chromatography (0-100% ethyl acetate inhexanes, then 0-35% methanol in DCM). LC-MS calculated for C₂₅H₃₁BClN₂O₄(M+H)⁺: m/z=469.2; found 469.2.

Step 4:(R)-5-((3-hydroxypyrrolidin-1-yl)methyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile

This compound was prepared using similar procedures as described forExample 126 with(R)-1-((7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)pyrrolidin-3-olreplacing(R)-1-((7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid in Step 5. LC-MS calculated for C₂₆H₃₁BN₃O₄ (M+H)⁺: m/z=460.2;found 460.2.

Step 5:(S)-1-(2-(2-(3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)pyrrolidine-3-carboxylicAcid

A microwave vial charged with(S)-1-(2-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)pyrrolidine-3-carboxylicacid (10.0 mg, 0.023 mmol),(R)-5-((3-hydroxypyrrolidin-1-yl)methyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile(10.58 mg, 0.023 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (1.812 mg, 2.303 μmol) and tripotassium phosphate hydrate (11.67mg, 0.051 mmol) was evacuated under high vacuum and refilled withnitrogen (repeated three times). 1,4-Dioxane (0.6 mL) and water (0.2 mL)was added and resulting mixture was stirred at 80° C. for 1 h. Thereaction mixture was diluted with methanol and 1 N HCl solution andpurified with prep-LCMS (pH 2) to give the desired product as the TFAsalt. LC-MS calculated for C₃₉H₃₉N₆O₆ (M+H)⁺: m/z=687.3; found 687.5.

Example 132(R)-1-(2-(2-(3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)pyrrolidine-3-carboxylicAcid

Step 1:(R)-1-(2-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 131 with (R)-pyrrolidine-3-carboxylic acid replacing(S)-pyrrolidine-3-carboxylic acid in Step 1 LC-MS calculated forC₁₉H₂₁BrN₃O₄ (M+H)⁺: m/z=434.1, 436.1; found 434.1, 436.1.

Step 2:(R)-1-(2-(2-(3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 131 with(R)-1-(2-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)pyrrolidine-3-carboxylicacid replacing(S)-1-(2-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)pyrrolidine-3-carboxylicacid in Step 5. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₃₉H₃₉N₆O₆ (M+H)⁺: m/z=687.3; found 687.5.

Example 133(S)-1-(2-(2-(3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)piperidine-2-carboxylicAcid

Step 1:(S)-1-(2-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)piperidine-2-carboxylicAcid

This compound was prepared using similar procedures as described forExample 131 with (S)-piperidine-2-carboxylic acid replacing(S)-pyrrolidine-3-carboxylic acid in Step 1 LC-MS calculated forC₂₀H₂₃BrN₃O₄ (M+H)⁺: m/z=448.1, 450.1; found 448.1, 450.1.

Step 2:(S)-1-(2-(2-(3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)piperidine-2-carboxylicAcid

This compound was prepared using similar procedures as described forExample 131 with(S)-1-(2-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)piperidine-2-carboxylicacid replacing(S)-1-(2-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)pyrrolidine-3-carboxylicacid in Step 5. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₄₀H₄₁N₆O₆ (M+H)⁺: m/z=701.3; found 701.3.

Example 134(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(3-(pyrrolidin-1-ylmethyl)-1,7-naphthyridin-8-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 24 with pyrrolidine replacing (R)-pyrrolidin-3-ol in Step 1. Thereaction mixture was diluted with MeOH and then purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as TFA salt.LC-MS calculated for C₄₁H₄₀N₇O₃ (M+H)⁺: m/z=678.3; found 678.3.

Example 135(R)-1-((2-(3′-(3-(azetidin-1-ylmethyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 24 with azetidine replacing (R)-pyrrolidin-3-ol in Step 1. Thereaction mixture was diluted with MeOH and then purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as TFA salt.LC-MS calculated for C₄₀H₃₈N₇O₃ (M+H)⁺: m/z=664.3; found 664.3.

Example 136(R)-1-((7-cyano-2-(3′-(3-((3-hydroxyazetidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 24 with 3-hydroxyazetidine replacing (R)-pyrrolidin-3-ol inStep 1. The reaction mixture was diluted with MeOH and then purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₄₀H₃₈N₇O₄ (M+H)⁺: m/z=680.3; found680.2.

Example 137(R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 24 with (R)-3-methylpyrrolin-3-ol replacing (R)-pyrrolidin-3-olin Step 1. The reaction mixture was diluted with MeOH and then purifiedby prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired productas TFA salt. LC-MS calculated for C₄₂H₄₂N₇O₄ (M+H)⁺: m/z=708.3; found708.3.

Example 138(R)-1-((7-cyano-2-(3′-(3-(((S)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:5-formyl-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile

To a solution of5-(hydroxymethyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile(Example 54, Step 2: 1.00 g, 2.56 mmol) in DCM (17.0 mL) was addedsodium bicarbonate (1.08 g, 12.81 mmol) followed by Dess-Martinperiodinane (1.30 g, 3.07 mmol). The mixture was stirred at r.t. for 1h. Then the mixture was loaded directly on silica gel. Purification ofthe mixture using EtOAc in DCM (0-30%) with 5% TEA by flashchromatography was performed. LCMS calculated for C₂₂H₂₂BN₂O₄ (M+H)⁺:m/z=389.2; found 389.2.

Step 2:(R)-1-((7-cyano-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of5-formyl-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile(901 mg, 2.321 mmol), (R)-pyrrolidine-3-carboxylic acid (534 mg, 4.64mmol) and triethylamine (647 μl, 4.64 mmol) in DCM (15.5 mL) was stirredat r.t. for 2 h. Then sodium triacetoxyborohydride (984 mg, 4.64 mmol)was added. The mixture was further stirred at r.t. for 1 h. The reactionwas diluted in DCM, washed with water. The aqueous solution was backextracted with DCM for six times. The combined organic phase wasconcentrated and used directly. LCMS calculated for C₂₇H₃₁BN₃O₅ (M+H)⁺:m/z=488.2; found 488.2.

Step 3:(S)-1-((8-(3-bromo-2-methylphenylamino)-1,7-naphthyridin-3-yl)methyl)-3-methylpyrrolidin-3-ol

This compound was prepared using similar procedure as described in Step1, Example 24 with (S)-3-methylpyrrolin-3-ol replacing(R)-pyrrolidin-3-ol. LC-MS calculated for C₂₁H₂₄BrN₄O (M+H)⁺: m/z=427.1,429.1; found 427.1, 429.1.

Step 4:(R)-1-((7-cyano-2-(3′-(3-(((S)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of(S)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)-3-methylpyrrolidin-3-ol(12 mg, 0.028 mmol),(R)-1-((7-cyano-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid (15 mg, 0.031 mmol), sodium carbonate (7.4mg, 0.070 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.2 mg,2.8 μmol) in water (50 μl) and 1,4-dioxane (250 μl) was purged with N₂and then stirred at 100° C. for 3 h. The reaction was cooled to roomtemperature and concentrated. The reaction mixture was diluted with MeOHand then purified by prep-HPLC (pH=10, acetonitrile/water+NH₄OH) to givethe desired product. LC-MS calculated for C₄₂H₄₂N₇O₄ (M+H)⁺: m/z=708.3;found 708.3.

Example 139(R)-1-((7-cyano-2-(3′-(7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:7-bromo-N-(3-chloro-2-methylphenyl)pyrido[3,2-d]pyrimidin-4-amine

In a vial, 3-chloro-2-methylaniline (92 mg, 0.65 mmol) and7-bromo-4-chloropyrido[3,2-d]pyrimidine (160 mg, 0.65 mmol) weresuspended in 2-propanol (3.25 mL). Sulfuric acid (0.035 ml, 0.65 mmol)was added to the reaction mixture. The resulting mixture was heated to100° C. for 1 h. The mixture was cooled, quenched with aqueous saturatedsodium bicarbonate, and diluted with DCM. The layers were separated andthe water layer was further extracted with DCM/2-propanol (3:1). Thecombined organic layers were dried over magnesium sulfate, filtered andconcentrated in vacuo. The crude solid was used directly. LC-MScalculated for C₁₄H₁₁BrClN₄ (M+H)⁺: m/z=349.0, 351.0; found 349.0,351.0.

Step 2:N-(3-chloro-2-methylphenyl)-7-vinylpyrido[3,2-d]pyrimidin-4-amine

A mixture of7-bromo-N-(3-chloro-2-methylphenyl)pyrido[3,2-d]pyrimidin-4-amine (149mg, 0.427 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (79 mg,0.51 mmol), sodium carbonate (113 mg, 1.069 mmol) andtetrakis(triphenylphosphine) palladium(0) (49 mg, 0.043 mmol) intert-butanol (855 μl) and water (855 μl) was degassed with N₂ andsealed. It was stirred at 80° C. for 2 h. The reaction mixture wascooled then extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude residue was used directly in the nextstep without further purification. LC-MS calculated for C₁₆H₁₄ClN₄(M+H)⁺: m/z=297.1; found 297.1.

Step 3:4-(3-chloro-2-methylphenylamino)pyrido[3,2-d]pyrimidine-7-carbaldehyde

A vial was charged withN-(3-chloro-2-methylphenyl)-7-vinylpyrido[3,2-d]pyrimidin-4-amine (0.121g, 0.408 mmol), a stir bar, THF (3.26 mL) and water (0.815 ml). To thissuspension was added osmium tetraoxide in water (4% w/w, 0.89 mL, 0.14mmol) followed by sodium periodate (0.436 g, 2.039 mmol) was added.After stirring at r.t. for 1 h, the reaction was quenched with asaturated aqueous solution of sodium thiosulfate. The mixture was thenextracted with ethyl acetate, and the combined organic layers wereseparated, washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude residue was used directly. LC-MScalculated for C₁₅H₁₂ClN₄O (M+H)⁺: m/z=299.1; found 299.0.

Step 4:(R)-1-((4-(3-chloro-2-methylphenylamino)pyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidin-3-ol

A mixture of4-((3-chloro-2-methylphenyl)amino)pyrido[3,2-d]pyrimidine-7-carbaldehyde(0.120 g, 0.402 mmol) and (R)-pyrrolidin-3-ol (0.070 g, 0.803 mmol) inDCM (2.68 ml) was stirred at r.t. for 2 h. Then sodiumtriacetoxyborohydride (0.170 g, 0.803 mmol) was added. The mixture wasfurther stirred at r.t. for 1 h. The reaction was diluted in DCM, washedwith water. The aqueous solution was extracted with DCM for three times.The combined organic phase was concentrated and purified by columnchromatography on silica gel (0-8% MeOH in DCM) to provide the desiredproduct as white foam. LC-MS calculated for C₁₉H₂₁ClN₅O (M+H)⁺:m/z=370.1; found 370.2.

Step 5:(R)-1-((7-cyano-2-(3′-(7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 138 with(R)-1-((4-(3-chloro-2-methylphenylamino)pyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidin-3-olreplacing(S)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)-3-methylpyrrolidin-3-oland dichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II)replacing tetrakis(triphenylphosphine)palladium(0) in Step 4. Thereaction was concentrated, then diluted in MeOH, filtered then purifiedby prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired productas TFA salt. LC-MS calculated for C₄₀H₃₉N₈O₄ (M+H)⁺: m/z=695.3; found695.3. ¹H NMR (500 MHz, DMSO) δ 10.31 (s, 1H), 9.05 (s, 1H), 8.62 (s,1H), 8.43 (d, J=1.9 Hz, 1H), 8.38 (d, J=1.3 Hz, 1H), 8.24-8.15 (m, 1H),8.12 (d, J=1.4 Hz, 1H), 7.69 (d, J=7.4 Hz, 1H), 7.58 (t, J=7.7 Hz, 1H),7.47 (d, J=6.5 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.13 (d, J=6.8 Hz, 1H),4.87-4.35 (m, 5H), 3.74-3.02 (m, 9H), 2.47 (s, 3H), 2.39-1.87 (m, 4H),1.98 (s, 3H).

Example 140(3R)-1-((7-cyano-2-(3′-(3-(1-((R)-3-hydroxypyrrolidin-1-yl)ethyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: N-(3-chloro-2-methylphenyl)-3-vinyl-1,7-naphthyridin-8-amine

This compound was prepared using similar procedures as described forExample 16 with 3-chloro-2-methylaniline replacing3-bromo-2-methylaniline in Step 2. LC-MS calculated for C₁₇H₁₅ClN₃(M+H)⁺: m/z=296.1; found 296.1.

Step 2:8-(3-chloro-2-methylphenylamino)-1,7-naphthyridine-3-carbaldehyde

A vial was charged withN-(3-chloro-2-methylphenyl)-3-vinyl-1,7-naphthyridin-8-amine (391 mg,1.322 mmol), a stir bar, 1,4-dioxane (10 mL) and water (3.3 mL). To thissuspension was added osmium tetroxide, 4% w/w in water (519 μl, 0.066mmol). The reaction was stirred for 5 min then sodium periodate (1414mg, 6.61 mmol) was added. After stirring at r.t. for 1 h, the reactionwas quenched with a saturated aqueous solution of sodium thiosulfate.The mixture was then extracted with ethyl acetate, and the combinedorganic layers were separated, washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude residue was useddirectly. LC-MS calculated for C₁₆H₁₃ClN₃O (M+H)⁺: m/z=298.1; found298.1.

Step 3:1-(8-(3-chloro-2-methylphenylamino)-1,7-naphthyridin-3-yl)ethanone

To a solution of8-((3-chloro-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde (76mg, 0.26 mmol) in THF (2.5 mL) was added methylmagnesium bromide (3.0 Min THF, 85 μl, 0.26 mmol) at 0° C. The mixture was stirred at thistemperature for 20 min. Then the reaction was quenched by EtOAc, washedwith water. The aqueous phase was extracted by EtOAc. The organic phasewas combined, dried over MgSO₄, and filtered. The filtrate wasconcentrated and used directly. LC-MS calculated for C₁₇H₁₇ClN₃O (M+H)⁺:m/z=314.1; found 314.1. To the above residue in DCM (2 mL) was addeddess-martin periodinane (141 mg, 0.332 mmol). The mixture was stirred atrt for 30 min. Then the reaction was quenched by NaHCO₃ sat. solutionand Na₂S₂O₃ solution, and extracted with DCM. The organic phase wasdried over MgSO₄ and filtered. The filtrate was concentrated and useddirectly. LC-MS calculated for C₁₇H₁₅ClN₃O (M+H)⁺: m/z=312.1; found312.1.

Step 4:(3R)-1-(1-(8-(3-chloro-2-methylphenylamino)-1,7-naphthyridin-3-yl)ethyl)pyrrolidin-3-ol

This compound was prepared using similar procedures as described forExample 16 with1-(8-(3-chloro-2-methylphenylamino)-1,7-naphthyridin-3-yl)ethanonereplacing8-(3-bromo-2-methylphenylamino)-1,7-naphthyridine-3-carbaldehyde in Step4. LC-MS calculated for C₂₁H₂₄ClN₄O (M+H)⁺: m/z=383.2; found 383.1.

Step 5:(3R)-1-((7-cyano-2-(3′-(3-(1-((R)-3-hydroxypyrrolidin-1-yl)ethyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 138 with(3R)-1-(1-(8-(3-chloro-2-methylphenylamino)-1,7-naphthyridin-3-yl)ethyl)pyrrolidin-3-olreplacing(S)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)-3-methylpyrrolidin-3-olandchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)replacing tetrakis(triphenylphosphine)palladium(0) in Step 4. Thereaction mixture was diluted with MeOH and then purified by prep-HPLC(pH=10, acetonitrile/water+NH₄OH) to give the desired product. LC-MScalculated for C₄₂H₄₂N₇O₄ (M+H)⁺: m/z=708.3; found 708.3.

Example 141(R)-1-((8-(3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:(R)-1-((8-(3-bromo-2-methylphenylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylic Acid

A mixture of8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde(Example 16, Step 3: 31 mg, 0.091 mmol) and (R)-pyrrolidine-3-carboxylicacid (20.9 mg, 0.181 mmol) in DCM (450 μl) was stirred at rt for 0.5 h.Then sodium triacetoxyborohydride (28.8 mg, 0.136 mmol) and acetic acid(8.0 μl, 0.14 mmol) was added. The mixture was further stirred at roomtemperature for 1 h. The reaction was quenched by water, and extractedwith DCM. The organic phased was dried over MgSO₄, filtered,concentrated and purified by column chromatography (0-10% MeOH in DCM).LC-MS calculated for C₂₁H₂₂BrN₄O₂ (M+H)⁺: m/z=441.1, 443.1; found 441.2,443.2.

Step 2:(R)-1-((8-(3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of(R)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylicacid (28 mg, 0.063 mmol),(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol(Example 1, Step 5; 28 mg, 0.070 mmol), sodium carbonate (16.8 mg, 0.159mmol) and tetrakis(triphenylphosphine)palladium(0) (5.1 mg, 4.4 μmol) inwater (106 μl) and 1,4-dioxane (529 μl) was purged with N₂ and thenstirred at 100° C. for 4 h. The reaction was cooled to room temperature.The reaction mixture was diluted with DCM and H₂O. The layers wereseparated. The aqueous layer was extracted with DCM three times. Theorganic layer was dried MgSO₄, filtered and concentrated to give a cruderesidue, which was purified by flash chromatography on a silica gelcolumn eluting with 0 to 14% MeOH/DCM to give the desired product. LC-MScalculated for C₃₆H₃₃ClN₅O₄ (M+H)⁺: m/z=634.2; found 634.3.

Step 3:(R)-1-((8-(3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution of(R)-1-((8-((3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylicacid (9 mg, 0.014 mmol) in DCM (142 μl) was added dess-martinperiodinane (7.2 mg, 0.017 mmol). The mixture was stirred at r.t. for 20min. The reaction was used directly for next step. LC-MS calculated forC₃₆H₃₁ClN₅O₄ (M+H)⁺: m/z=632.2; found 632.2.

Step 4:(R)-1-((8-(3′-(7-chloro-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of(R)-1-((8-((3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylicacid (8.3 mg, 0.013 mmol) and (R)-pyrrolidin-3-ol (2.3 mg, 0.026 mmol)in DCM (66.0 μl) was stirred at r.t. for 0.5 h. Then sodiumtriacetoxyborohydride (4.20 mg, 0.020 mmol) was added. The mixture wasfurther stirred at r.t. for 1 h. The reaction was quenched by water, andextracted with DCM five times. The organic layer was dried over MgSO₄,then filtered, concentrated to provide a crude product, which was useddirectly. LC-MS calculated for C₄₀H₄₀ClN₆O₄ (M+H)⁺: m/z=703.3; found703.3.

Step 5:(R)-1-((8-(3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of(R)-1-((8-((3′-(7-chloro-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylicacid (5.8 mg, 8.2 μmol), potassium ferrocyanide(II) hydrate (3.5 mg, 8.2μmol), potassium acetate (0.40 mg, 4.1 μmol) andmethanesulfonato(2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(1.310 mg, 1.650 μmol) in 1,4-dioxane (41 μl) and water (41 μl) wasstirred and heated at 80° C. for 4 h. After cooling to r.t., thereaction was concentrated, then diluted in MeOH, filtered then purifiedby prep-HPLC (pH=10, acetonitrile/water+NH₄OH) to give the desiredproduct. LC-MS calculated for C₄₁H₄₀N₇O₄ (M+H)⁺: m/z=694.3; found 694.3.

Example 142(S)-1-((2-(2′-chloro-3′-(5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:N-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide

To a solution of tert-butyl2-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(Example 92, Step 1: 140 mg, 0.211 mmol) in DCM (3 mL) was addedtrifluoroacetic acid (1.0 mL). The solution was stirred at r.t. for 1hour, then concentrate to dryness. To a solution of above residue in DCM(5.00 mL) was added TEA (0.059 mL, 0.423 mmol), then acetaldehyde (0.060mL, 1.056 mmol). After the reaction mixture was stirred at r.t. 30 min,sodium triacetoxyborohydride (134 mg, 0.634 mmol) was added. The mixturewas stirred at r.t. 2 hours, quenched with sat. NH₄Cl solution, andextracted with DCM. The combined extracts were washed with water andbrine, dried over MgSO₄, filtered and concentrated under reducedpressure. The residue was purified by flash chromatography on a silicagel column eluting with 10% MeOH in DCM to afford the desired product.LC-MS calculated for C₃₁H₃₀Cl₂N₅O₃ (M+H)⁺: m/z=590.2; found 590.1.

Step 2:N-(2-chloro-3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide

This compound was prepared using similar procedures as described forExample 12 withN-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamidereplacing(7-chloro-2-(2,2′-dimethyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanolin Step 1. LC-MS calculated for C₃₂H₃₀ClN₆O₃ (M+H)⁺: m/z=581.2; found581.2

Step 3:N-(2-chloro-3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide

To a stirred solution ofN-(2-chloro-3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide(60.0 mg, 0.103 mmol) in DCM (3.0 ml) was added sodium bicarbonate (87mg, 1.033 mmol) and dess-martin periodinane (65.7 mg, 0.155 mmol). Theresulted mixture was stirred at r.t. for 2 h. The reaction mixture wasdiluted with water then extracted with DCM. The combined extracts werewashed with water and brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. The residue was used in the next step directly.LC-MS calculated for: C₃₂H₂₈ClN₆O₃: m/z=579.2; found 579.2.

Step 4:(S)-1-((2-(2′-chloro-3′-(5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution ofN-(2-chloro-3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide(10 mg, 0.017 mmol) in DCM (1 ml) was added (S)-pyrrolidine-3-carboxylicacid (9.94 mg, 0.086 mmol) and DIEA (0.024 ml, 0.138 mmol), the mixturewas stirred at r.t. 60 min, then sodium triacetoxyborohydride (10.98 mg,0.052 mmol) was added, and continue to stirred at r.t. over night. Thereaction mixture was concentrated, and the residue was dissolved in MeOHand then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to givethe desired product as TFA salt. LC-MS calculated for C₃₇H₃₇ClN₇O₄(M+H)⁺: m/z=678.3; found 678.3.

Example 143(R)-1-((2-(2′-chloro-3′-(5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 147 with (R)-pyrrolidine-3-carboxylic acid replacing(S)-pyrrolidine-3-carboxylic acid in Step 4. The reaction mixture wasconcentrated, the residue was dissolved in MeOH and then purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₃₇H₃₇ClN₇O₄ (M+H)⁺: m/z=678.3; found678.3.

Example 144(S)-1-((7-cyano-2-(3′-((4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: 8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-4(1H)-one

A mixture of 3-bromo-2-methylaniline (280.0 mg, 1.505 mmol),8-chloro-1,7-naphthyridin-4(1H)-one (272 mg, 1.505 mmol) and 4M HCl indioxane (376 μL) was heated in tert-butanol (7.5 mL) at 120° C. for 2hours. After the reaction mixture was cooled to r.t., it wasconcentrated to dryness and used in the next step directly withoutfurther purification. LC-MS calculated for C₁₅H₁₃BrN₃O (M+H)⁺:m/z=330.0, 332.0; found 330.0, 332.0.

Step 2: N-(3-bromo-2-methylphenyl)-4-chloro-1,7-naphthyridin-8-amine

Phosphoryl chloride (0.494 mL, 5.30 mmol) was added to a mixture of8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-4(1H)-one (350 mg,1.060 mmol), benzyltriethylammonium chloride (483 mg, 2.120 mmol) andN,N-diethylaniline (0.253 mL, 1.590 mmol) in acetonitrile (10 mL) andthen the reaction was stirred at 80° C. for 1 h. The solvent was thenremoved, and the residue was diluted with DCM, washed with sat'd NaHCO₃aqueous solution, water, brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography on asilica gel column eluting with 2% ethyl acetate in DCM to afford thedesired product. LCMS calculated for C₁₅H₁₂BrClN₃ (M+H)⁺: m/z=348.0,350.0, found 348.0, 350.0.

Step 3:(7-chloro-2-(2,2′-dimethyl-3′-((4-vinyl-1,7-naphthyridin-8-yl)amino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanol

The mixture ofN-(3-bromo-2-methylphenyl)-4-chloro-1,7-naphthyridin-8-amine (130 mg,0.373 mmol),(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol(Example 1, Step 5; 149 mg, 0.373 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (18.27 mg, 0.022 mmol) and sodium carbonate (119mg, 1.119 mmol) in dioxane (5.0 mL) and water (1.0 mL) was vacuumed andrefilled with N₂. Then the mixture was stirred at 90° C. for 2 hs. Afterthe reaction mixture was cooled to r.t., to this reaction mixture wasadded 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (115 mg, 0.746mmol) and another portion of catalyst. The reaction mixture was degassedwith N₂ and heated at 100° C. for another 5 hours. After being cooled toroom temperature, the reaction mixture was concentrated under reducedpressure. The residue was purified by flash chromatography on a silicagel column eluting with 20% AcOEt in DCM to afford the desired product.LC-MS calculated for C₃₂H₂₆ClN₄O₂ (M+H)⁺: m/z=533.2; found 533.2

Step 4:8-((3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)amino)-1,7-naphthyridine-4-carbaldehyde

To a solution of(7-chloro-2-(2,2′-dimethyl-3′-((4-vinyl-1,7-naphthyridin-8-yl)amino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanol(200 mg, 0.375 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was addedosmium tetraoxide (4% w/w in water, 0.014 ml) at room temperature. Themixture was stirred for 10 min and then sodium periodate (241 mg, 1.126mmol) was added. The reaction mixture was stirred at r.t. for 2 hours.The reaction mixture was diluted with water then extracted with DCM. Thecombined extracts were washed with water and brine, dried over MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column eluting with 25%AcOEt in DCM to afford the desired product. LC-MS calculated forC₃₁H₂₄ClN₄O₃ (M+H)⁺: m/z=535.1; found 535.1

Step 5:(S)-1-((8-((3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)amino)-1,7-naphthyridin-4-yl)methyl)pyrrolidin-3-ol

To a solution of8-((3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)amino)-1,7-naphthyridine-4-carbaldehyde(100 mg, 0.187 mmol) in DCM (4 mL) was added (S)-pyrrolidin-3-ol (32.6mg, 0.374 mmol), the mixture was stirred at r.t. 10 min, then sodiumtriacetoxyborohydride (119 mg, 0.561 mmol) was added, continue to stirat r.t. over night. The reaction mixture was diluted with water thenextracted with DCM. The combined extracts were washed with water andbrine, dried over MgSO₄, filtered and concentrated under reducedpressure to afford the desired compound, which was used for next stepwithout further purification. LC-MS calculated for C₃₅H₃₃ClN₅O₃ (M+H)⁺:m/z=606.2; found 606.2

Step 6:(S)-7-chloro-2-(3′-((4-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-5-carbaldehyde

A suspensionof(S)-1-((8-((3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)amino)-1,7-naphthyridin-4-yl)methyl)pyrrolidin-3-ol(80 mg, 0.132 mmol) and manganese(IV) oxide (229 mg, 2.64 mmol) in DCM(10 ml) was stirred at 45° C. for 3 hours. After cooling, the solid wasfiltered off and washed with DCM thoroughly. The filtrate wasconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column eluting with 10% MeOH in DCM toafford the desired product. LC-MS calculated for C₃₅H₃₁ClN₅O₃ (M+H)⁺:m/z=604.2; found 604.2

Step 7:(S)-5-formyl-2-(3′-((4-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile

This compound was prepared using similar procedures as described forExample 12 with(S)-7-chloro-2-(3′-((4-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-5-carbaldehydereplacing(7-chloro-2-(2,2′-dimethyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanolin Step 1. LC-MS calculated for: C₃₆H₃₁N₆O₃: m/z=595.2; found 595.2

Step 8:(S)-1-((7-cyano-2-(3′-((4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution of(S)-5-formyl-2-(3′-((4-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile(10 mg, 0.017 mmol) in DCM (1 ml) was added (S)-pyrrolidine-3-carboxylicacid (9.68 mg, 0.084 mmol) and DIEA (0.023 ml, 0.135 mmol), the mixturewas stir at r.t. 60 min, then sodium triacetoxyborohydride (10.69 mg,0.050 mmol) was added, and continued to stir at r.t. overnight. Thereaction was concentrated, then diluted in MeOH, filtered, and thenpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as TFA salt. LC-MS calculated for C₄₁H₄₀N₇O₄ (M+H): m/z=694.3;found 694.3.

Example 145(R)-1-((7-cyano-2-(3′-((4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 144 with (R)-pyrrolidine-3-carboxylic acid replacing(S)-pyrrolidine-3-carboxylic acid in Step 8. The reaction wasconcentrated, then diluted in MeOH, filtered then purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as TFA salt.LC-MS calculated for C₄₁H₄₀N₇O₄ (M+H): m/z=694.3; found 694.3.

Example 146(R)-1-((7-cyano-2-(3′-((3-((((S)-2-hydroxypropyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:N-(3-bromo-2-methylphenyl)-3-(chloromethyl)-1,7-naphthyridin-8-amine

To a solution of(8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methanol(Affinity Research Chemicals, cat #ARI-0169: 200 mg, 0.581 mmol) in DCM(5 ml) was added thionyl chloride (51 μl, 0.699 mmol) dropwise. Thereaction mixture was stirred at r.t. 30 minutes. LC/MS check reactioncompleted. The reaction mixture was concentrated to dryness underreduced pressure. The residue was washed with hexanes, filtered toafford the desired compound and used in the next step directly. LC-MScalculated for C₁₆H₁₄BrClN₃ (M+H)⁺: m/z=362.0, 364.0; found 362.0, 364.0

Step 2:(S)-1-(((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)amino)propan-2-ol

To a solution ofN-(3-bromo-2-methylphenyl)-3-(chloromethyl)-1,7-naphthyridin-8-amine (15mg, 0.041 mmol) in ACN (1 ml) was added DIEA (0.022 ml, 0.124 mmol)and(S)-1-aminopropan-2-ol (3.11 mg, 0.041 mmol), the mixture was stir at60° C. overnight. The reaction mixture was diluted with water and thenextracted with DCM. The combined extracts were washed with NaHCO₃aqueous solution and brine, dried over MgSO₄, filtered and concentratedunder reduced pressure to afford the desired product, which was used inthe next step without further purification. LC-MS calculated forC₁₉H₂₂BrN₄O (M+H)⁺: m/z=401.1, 403.1; found 401.1, 403.1

Step 3:(R)-1-((7-cyano-2-(3′-((3-((((S)-2-hydroxypropyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 138 with(S)-1-(((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)amino)propan-2-olreplacing(S)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)-3-methylpyrrolidin-3-olin Step 4. The reaction was concentrated, then diluted in MeOH,filtered, and then purified by prep-HPLC (pH=2, acetonitrile/water+TFA)to give the desired product as TFA salt. LC-MS calculated for C₄₀H₄₀N₇O₄(M+H)⁺: m/z=682.2; found 682.2.

Example 147(R)-1-((7-cyano-2-(3′-((3-((((R)-2-hydroxypropyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 146 with(R)-1-(((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)amino)propan-2-olreplacing(S)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)-3-methylpyrrolidin-3-olin Step 3. The reaction was concentrated, then diluted in MeOH, filteredthen purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as TFA salt. LC-MS calculated for C₄₀H₄₀N₇O₄ (M+H)⁺:m/z=682.2; found 682.2.

Example 148(R)-1-((7-chloro-2-(3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)phenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: 4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-hydroxybenzaldehyde

To a mixture of (3-bromo-2-methylphenyl)methanol (2.330 g, 11.59 mmol),5-chloro-2,4-dihydroxybenzaldehyde (2.0 g, 11.59 mmol) andtriphenylphosphine (3.65 g, 13.91 mmol) in THF (10 ml) at 0° C. wasadded diisopropyl azodicarboxylate (2.93 ml, 15.07 mmol). The mixturewas stirred at room temperature overnight. The mixture was concentratedand diluted with EtOAc. The solid was collected by filtration to givethe desired ether (2.0 g, 5.62 mmol, 48.5% yield). LCMS calculated forC₁₅H₁₃BrClO₃ (M+H)+: m/z=357.2; found 357.2.

Step 2:5-((5-((3-bromo-2-methylbenzyl)oxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile

A mixture of4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-hydroxybenzaldehyde (2.0 g,5.62 mmol), 5-(chloromethyl)nicotinonitrile (0.927 g, 6.07 mmol) andcesium carbonate (2.75 g, 8.44 mmol) in DMF (12 ml) was stirred at 70°C. for 3 hours. The mixture was poured into water. The solid wascollected by filtration and air dried to give the desired aldehyde (2.2g, 4.66 mmol, 83% yield). LCMS calculated for C₂₂H₁₇BrClN₂O₃ (M+H)+:m/z=473.0; found 473.0.

Step 3:(R)-1-((7-chloro-2-(3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of5-((5-((3-bromo-2-methylbenzyl)oxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile(30 mg, 0.064 mmol),(R)-1-((7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (Example 126, Step 4; 37.9 mg, 0.076 mmol), potassium carbonate(17.58 mg, 0.127 mmol) and(1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (4.65 mg,6.36 μmol) in 1,4-dioxane (3 ml) and water (0.60 ml) was purged withnitrogen, and heated at 95° C. for 2 hours. The mixture was purified onprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired acid (11mg, 0.014 mmol, 22.71% yield). LCMS calculated for C₄₂H₃₅Cl₂N₄O₆ (M+H)+:m/z=761.2; found 761.2.

Step 4:(R)-1-((7-chloro-2-(3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)phenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Sodium triacetoxyborohydride (1.252 mg, 5.91 μmol) was added to amixture of(R)-1-((7-chloro-2-(3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (3.0 mg, 3.9 μmol), (R)-pyrrolidin-3-ol (0.34 mg, 3.9 μmol) andtriethylamine (1.1 μl, 7.9 μmol) in DCM (1.0 ml). After stirring at roomtemperature for 2 hours, the mixture was purified on prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₄₆H₄₄Cl₂N₅O₆ (M+H)+: m/z=832.2; found 832.2.

Example 149(S)-1-(4-((3′-(5-(((R)-3-carboxypyrrolidin-1-yl)methyl)-7-chlorobenzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylicAcid

Sodium triacetoxyborohydride (1.25 mg, 5.91 μmol) was added to a mixtureof(R)-1-((7-chloro-2-(3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (Example 148, Step 3: 3.0 mg, 3.9 μmol),(S)-piperidine-2-carboxylic acid (0.76 mg, 5.9 μmol) and triethylamine(1.1 μl, 7.9 μmol) in DCM (1.0 ml). After stirring at room temperaturefor 2 hours, the mixture was purified on prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₄₈H₄₆Cl₂N₅O₇ (M+H)+: m/z=874.2; found 874.2.

Example 150(R)-1-((7-chloro-2-(3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(((2-hydroxyethyl)amino)methyl)phenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 148 with 2-aminoethan-1-ol replacing (R)-pyrrolidin-3-ol in Step4. The reaction was concentrated, then diluted in MeOH, filtered thenpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as TFA salt. LC-MS calculated for C₄₄H₄₂Cl₂N₅O₆ (M+H)+:m/z=806.2; found 806.2.

Example 151(R)-1-((5-(2-chloro-3′-(7-chloro-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic Acid

Methyl iodide (1.71 ml, 27.5 mmol) was added to a mixture of5-bromo-2-hydroxynicotinic acid (5.00 g, 22.94 mmol) and potassiumcarbonate (4.75 g, 34.4 mmol) in MeOH (76.0 mL). The reaction mixturewas stir at 80° C. for 10 hrs. The reaction was cooled to roomtemperature and the solvent was concentrated under reduced pressure.Water was added, and the mixture was washed with DCM twice. To theaqueous phase was added 1 M aqueous solution of HCl until the pH=2.Then, the acidic aqueous layer was extracted with DCM twice. The organicphase was dried over MgSO₄, filtered and the filtrate was concentrated.The crude residue was used directly in the next step without furtherpurification. LC-MS calculated for C₇H₇BrNO₃ (M+H)⁺: m/z=232.0, 234.0;found 232.0, 234.0.

Step 2: 1-methyl-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic Acid

A mixture of 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylicacid (321 mg, 1.385 mmol),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (213 mg, 1.385 mmol),sodium carbonate (440 mg, 4.15 mmol) andtetrakis(triphenylphosphine)palladium(0) (80 mg, 0.069 mmol) int-butanol (1.4 ml) and water (1.4 ml) was degassed and sealed. It wasstirred at 80° C. for 2 h. The reaction was cooled to room temperatureand the solvent was concentrated under reduced pressure. Water wasadded, and the mixture was washed with DCM twice. To the aqueous phasewas added 1 M aqueous solution of HCl until the pH=2. Then, the acidicaqueous layer was extracted with DCM twice. The organic phase was driedover MgSO₄, filtered and the filtrate was concentrated. The cruderesidue was used directly in the next step without further purification.LC-MS calculated for C₉H₁₀NO₃ (M+H)⁺: m/z=180.1; found 180.1.

Step 3:N-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)-1-methyl-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxamide

To a solution of 1-methyl-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylicacid (30.0 mg, 0.170 mmol),(2-(3′-amino-2′-chloro-2-methyl-[1,1′-biphenyl]-3-yl)-7-chlorobenzo[d]oxazol-5-yl)methanol(Example 15, Step 1: 68.0 mg, 0.17 mmol), and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (78.0 mg, 0.204 mmol) in 1,2-dichloroethane (2.2ml) was added N,N-diisopropylethylamine (60 μl, 0.34 mmol). The mixturewas stirred at room temperature for 2 hrs. Then, the mixture was dilutedwith DCM, and washed with water and brine. The organic phase was driedover MgSO₄ before filtering. The filtrate was concentrated and purifiedby flash chromatography to afford the desired product. LC-MS calculatedfor C₃₀H₂₄Cl₂N₃O₄ (M+H)⁺: m/z=560.1; found 560.1.

Step 4:N-(2-chloro-3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)-1-methyl-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxamide

To a stirred solution ofN-(2-chloro-3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)-1-methyl-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxamide(86.0 mg, 0.153 mmol) in DCM (3.0 ml) was added Dess-Martin Periodinane(65.0 mg, 0.153 mmol). The resulted mixture was stirred at r.t. for 2hrs, and then filtered. The filtrate was concentrated under reducedpressure. The residue was used in the next step directly without furtherpurification. LC-MS calculated for C₃₀H₂₂Cl₂N₃O₄ (M+H)⁺: m/z=558.1;found 558.1.

Step 5:(R)—N-(2-chloro-3′-(7-chloro-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)-1-methyl-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxamide

A mixture ofN-(2-chloro-3′-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)-1-methyl-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxamide(47 mg, 0.085 mmol) and (R)-pyrrolidin-3-ol (22.0 mg, 0.255 mmol) in THF(0.85 mL) was stirred at room temperature for 0.5 h. Then sodiumtriacetoxyborohydride (54 mg, 0.255 mmol) was added. The mixture wasfurther stirred at room temperature for 1 h. The reaction mixture wasquenched by NH₄OH aqueous solution then extracted with DCM. The organicphases were combined and dried over MgSO₄, then filtered. The filtratewas concentrated and used directly in the next step without furtherpurification. LC-MS calculated for C₃₄H₃₁Cl₂N₄O₄ (M+H)⁺: m/z=629.2;found 629.2.

Step 6:(R)—N-(2-chloro-3′-(7-chloro-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)-5-formyl-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

A vial was charged with(R)—N-(2-chloro-3′-(7-chloro-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)-1-methyl-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxamide(50 mg, 0.08 mmol), a stir bar, 1,4-dioxane (0.6 ml) and water (0.2 ml).To this suspension was added potassium osmate dihydrate (1.5 mg, 0.004mmol). The reaction was stirred for 5 min, and then sodium periodate (86mg, 0.4 mmol) was added. After stirring at room temperature for 1 h, thereaction mixture was quenched with a saturated aqueous solution ofsodium thiosulfate. The mixture was then extracted with ethyl acetate,and the combined organic layers were separated, washed with brine, driedover Na₂SO₄, filtered, and concentrated in vacuo. The crude residue waspurified by flash chromatography on a silica gel column eluting with 0to 6% MeOH in DCM to afford the desired product. LC-MS calculated forC₃₃H₂₉Cl₂N₄O₅ (M+H)⁺: m/z=631.1; found 631.1.

Step 7:(R)-1-((5-(2-chloro-3′-(7-chloro-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of(R)—N-(2-chloro-3′-(7-chloro-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)-5-formyl-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(51 mg, 0.08 mmol) and (R)-pyrrolidine-3-carboxylic acid (9.21 mg, 0.08mmol) in THF (0.5 mL) was stirred at room temperature for 0.5 h. Thensodium triacetoxyborohydride (51 mg, 0.24 mmol) was added. The mixturewas further stirred at room temperature for 1 h. The mixture wasconcentrated and diluted with MeOH and then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₃₈H₃₈Cl₂N₅O₆ (M+H)⁺: m/z=730.2; found 730.2.

Example 152(S)-1-((7-cyano-2-(3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)imidazo[1,2-a]pyrazin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: 8-chloro-3-vinylimidazo[1,2-a]pyrazine

A mixture of 3-bromo-8-chloroimidazo[1,2-a]pyrazine (400 mg, 1.721 mmol)(Ark Pharm, cat #AK-24131),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (350 μL, 2.065 mmol),sodium carbonate (456 mg, 4.30 mmol) andtetrakis(triphenylphosphine)palladium(0) (99 mg, 0.086 mmol) intert-butanol (4.0 mL) and water (4.0 mL) was purged with nitrogen andthen stirred at 100° C. for 2 h. The reaction mixture was cooled thenextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by flash chromatography on a silicagel column eluting with 50% ethyl acetate in hexanes to afford thedesired product. LC-MS calculated for C₈H₇ClN₃ (M+H)⁺: m/z=180.0; found180.1.

Step 2: N-(3-bromo-2-methylphenyl)-3-vinylimidazo[1,2-a]pyrazin-8-amine

A mixture of 3-bromo-2-methylaniline (120 mg, 0.645 mmol),8-chloro-3-vinylimidazo[1,2-a]pyrazine (Step 1: 139 mg, 0.774 mmol) andHCl in dioxane (4.0 M, 161 μL, 0.645 mmol) in tert-butanol (3.2 mL) washeated at 100° C. for 1 h. The reaction was then cooled to roomtemperature and diluted with dichloromethane. The reaction was quenchedby aqueous NaHCO₃ solution and extracted with dichloromethane. Theorganic phase was dried over Na₂SO₄, filtered and the filtrate wasconcentrated. The residue was used directly for next step. LC-MScalculated for C₁₅H₁₄BrN₄ (M+H)⁺: m/z=329.0/331.0; found 329.1/331.1.

Step 3:8-((3-bromo-2-methylphenyl)amino)imidazo[1,2-a]pyrazine-3-carbaldehyde

Osmium tetroxide (4% w/w in water, 0.253 ml, 0.032 mmol) was added to amixture ofN-(3-bromo-2-methylphenyl)-3-vinylimidazo[1,2-a]pyrazin-8-amine (Step 2:0.212 g, 0.645 mmol) in 1,4-dioxane (4.8 mL) and water (1.6 mL). Thereaction was stirred for 5 min then sodium periodate (0.690 g, 3.23mmol) was added. After being stirred at room temperature for 1 h, thereaction was quenched with a saturated aqueous solution of sodiumthiosulfate. The mixture was then extracted with ethyl acetate, and thecombined organic layers were separated, washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The cruderesidue was used directly for next step. LC-MS calculated forC₁₄H₁₂BrN₄O (M+H)+: m/z=331.0/333.0; found 331.0/333.0.

Step 4:(S)-1-((8-((3-bromo-2-methylphenyl)amino)imidazo[1,2-a]pyrazin-3-yl)methyl)pyrrolidin-3-ol

A mixture of8-((3-bromo-2-methylphenyl)amino)imidazo[1,2-a]pyrazine-3-carbaldehyde(Step 3: 166 mg, 0.5 mmol) and (S)-pyrrolidin-3-ol (131 mg, 1.500 mmol)in dichloromethane (5.0 mL) was stirred at room temperature for 2 h.Then sodium triacetoxyborohydride (318 mg, 1.500 mmol) and acetic acid(86 μL, 1.500 mmol) were added. The mixture was further stirred at roomtemperature for 1 h. The reaction was quenched by NH₄OH aqueous solutionand extracted with dichloromethane. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography on asilica gel column eluting with 10% methanol in dichloromethane to affordthe desired product. LCMS calculated for C₁₈H₂₁BrN₅O (M+H)⁺:m/z=402.1/404.1; found 402.1/404.1.

Step 5:(S)-1-((8-((3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)amino)imidazo[1,2-a]pyrazin-3-yl)methyl)pyrrolidin-3-ol

A mixture of(S)-1-((8-((3-bromo-2-methylphenyl)amino)imidazo[1,2-a]pyrazin-3-yl)methyl)pyrrolidin-3-ol(Step 4: 50 mg, 0.124 mmol),(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol(Example 1, Step 5: 49.7 mg, 0.124 mmol), sodium carbonate (32.9 mg,0.311 mmol) and tetrakis(triphenylphosphine)palladium(0) (14.36 mg,0.012 mmol) in water (0.2 mL) and 1,4-dioxane (1.0 mL) was purged withnitrogen and then stirred at 100° C. for 4 h. After being cooled to roomtemperature, the reaction mixture was extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column eluting with 10%methanol in dichloromethane to afford the desired product. LC-MScalculated for C₃₃H₃₂ClN₆O₃ (M+H)⁺: m/z=595.2; found 595.1.

Step 6:(S)-5-(hydroxymethyl)-2-(3′-((3-((3-hydroxypyrrolidin-1-yl)methyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile

This compound was prepared using similar procedures as described forExample 12 with(S)-1-((8-((3′-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)amino)imidazo[1,2-a]pyrazin-3-yl)methyl)pyrrolidin-3-olreplacing(7-chloro-2-(2,2′-dimethyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanolin Step 1. LC-MS calculated for C₃₄H₃₂N₇O₃ (M+H)⁺: m/z=586.3; found586.5.

Step 7:(S)-5-formyl-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)imidazo[1,2-a]pyrazin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile

A suspension of(S)-5-(hydroxymethyl)-2-(3′-((3-((3-hydroxypyrrolidin-1-yl)methyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile(Step 6: 20 mg, 0.034 mmol) and manganese dioxide (44.5 mg, 0.512 mmol)in dichloromethane (0.25 mL) was stirred at 45° C. for 30 min. Thereaction was filtered through a short pad of celite and thenconcentrated to yield a crude residue, which was used directly withoutfurther purification. LC-MS calculated for C₃₄H₃₀N₇O₃ (M+H)⁺: m/z=584.2;found 584.3.

Step 8:(S)-1-((7-cyano-2-(3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)imidazo[1,2-a]pyrazin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of(S)-5-formyl-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)imidazo[1,2-a]pyrazin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile(Step 7: 20.00 mg, 0.034 mmol) and (S)-pyrrolidine-3-carboxylic acid(3.93 mg, 0.034 mmol) in dichloromethane (0.25 mL) was stirred at roomtemperature for 1 h. Then sodium triacetoxyborohydride (7.24 mg, 0.034mmol) and acetic acid (1.955 μL, 0.034 mmol) was added. After beingstirred at room temperature for 1 h, the reaction mixture was dilutedwith MeOH, and purified via pH 2 preparative HPLC (MeCN/water with TFA)to give the desired product as TFA salt. LC-MS calculated for C₃₉H₃₉N₈O₄(M+H)⁺: m/z=683.3; found 683.5.

Example 1531-((7-chloro-2-(2′-chloro-3′-((5-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-3-methylpyrazin-2-yloxy)methyl)-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: (2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazol-5-yl)methylMethanesulfonate

To a solution of(2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazol-5-yl)methanol(Example 1, Step 4: 2.0 g, 5.67 mmol) in DCM (30.0 ml) was addedtriethylamine (1.186 ml, 8.51 mmol) with stirring at r.t., followed byaddition of methanesulfonyl chloride (0.530 ml, 6.81 mmol). The solutionwas vigorously stirred at r.t. for 2 hours. It was diluted with DCM,washed with water (×2), brine; dried over Na₂SO₄. After filtration, thefiltrate was concentrated and the residue was used directly. LC-MScalculated for C₁₆H₁₄BrClNO₄S (M+H)⁺: m/z=432.0; found 431.9.

Step 2: tert-butyl1-((2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylate

To a solution of(2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazol-5-yl)methylmethanesulfonate (400 mg, 0.929 mmol) andtert-butylpyrrolidine-3-carboxylate (184 mg, 1.022 mmol) in DCM (15.00ml) was added sodium carbonate (295 mg, 2.79 mmol) with stirring at r.t.The suspension was vigorously stirred at r.t. for 2 hours. Afterfiltration, the filtrate was concentrated. The crude material waspurified by flash column. LC-MS calculated for C₂₄H₂₇BrClN₂O₃ (M+H)⁺:m/z=507.1; found 507.0.

Step 3: tert-butyl1-((7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylate

A mixture of tert-butyl1-((2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylate(300 mg, 0.593 mmol), bis(pinacolato)diboron (181 mg, 0.712 mmol) andpotassium acetate (87 mg, 0.890 mmol) in dioxane (3 ml) in a glass vialwas degassed for 5 min. Then to the mixture was addedtricyclohexylphosphine (11.64 mg, 0.042 mmol), followed bytris(dibenzylideneacetone)dipalladium(0) (32.6 mg, 0.036 mmol). Themixture was degassed for another 2 min. It was sealed and stirred at120° C. for 1.5 hours. LCMS showed product formed. After cooling, thereaction mixture was concentrated. The crude material was purified byflash column eluting with EA/hexanes 0-100%. LC-MS calculated forC₃₀H₃₉BClN₂O₅ (M+H)⁺: m/z=553.3; found 553.3.

Step 4: methyl5-(3-bromo-2-chlorobenzyloxy)-6-methylpyrazine-2-carboxylate

A mixture of (3-bromo-2-chlorophenyl)methanol (534 mg, 2.412 mmol) andsodium hydride (90 mg, 60% dispersion in mineral oil, 2.251 mmol) inN,N-dimethylformamide (5 ml) was stirred at r.t. for 30 min. Then to themixture was added methyl 5-chloro-6-methylpyrazine-2-carboxylate (300mg, 1.608 mmol). The mixture was stirred at r.t. for 1 hr. LCMS showedproduct formed. It was quenched with water, extracted with EA. Afterseparation, the organic solution was washed with water (×2), brine;dried over Na₂SO₄. After filtration, the filtrate was concentrated toyield crude material, which was purified by flash column. LC-MScalculated for C₁₄H₁₃BrClN₂O₃ (M+H)⁺: m/z=373.0; found 373.0.

Step 5: (5-(3-bromo-2-chlorobenzyloxy)-6-methylpyrazin-2-yl)methanol

To a solution of methyl5-((3-bromo-2-chlorobenzyl)oxy)-6-methylpyrazine-2-carboxylate (0.58 g,1.561 mmol) in THF (10 ml) was added dropwisely lithium aluminum hydridein THF (1N, 1.093 ml, 1.093 mmol) with stirring at 0° C. The reactionwas stirred at this temperature for 1 hr. Then it was diluted with EA,washed with water (×2), brine; and dried over Na₂SO₄. After filtration,the filtrate was concentrated and the residue was used directly. LC-MScalculated for C₁₃H₁₃BrClN₂O₂ (M+H)⁺: m/z=345.0; found 345.0.

Step 6: 5-(3-bromo-2-chlorobenzyloxy)-6-methylpyrazine-2-carbaldehyde

To a solution of(5-((3-bromo-2-chlorobenzyl)oxy)-6-methylpyrazin-2-yl)methanol (0.50 g,1.46 mmol) in DCM (20 ml) was added Dess-Martin periodinane (0.541 ml,1.746 mmol). The mixture was stirred at r.t. for 2 hrs. Then it wasdiluted with DCM, and quenched with sat'd NaHCO₃ solution. Afterseparation, the organic solution was washed with water, brine, and driedover Na₂SO₄. After filtration, the filtrate was concentrated. The crudematerial was purified by flash column to yield the title compound. LC-MScalculated for C₁₃H₁₁BrClN₂O₂ (M+H)⁺: m/z=343.0; found 342.9.

Step 7: tert-butyl1-((7-chloro-2-(2′-chloro-3′-((5-formyl-3-methylpyrazin-2-yloxy)methyl)-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylate

A mixture of tert-butyl1-((7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylate(220 mg, 0.398 mmol),5-((3-bromo-2-chlorobenzyl)oxy)-6-methylpyrazine-2-carbaldehyde (150 mg,0.438 mmol) and cesium carbonate (324 mg, 0.995 mmol) in t-BuOH (0.8 ml)and water (0.200 ml) was degassed with N₂ for 3 min, and then to themixture was added 1,1′-bis(di-cyclohexylphosphino)ferrocene palladiumdichloride (30.1 mg, 0.040 mmol). The resulting mixture was degassedwith N₂ for another 2 min. Then it was sealed and stirred at 68° C. for2 hours. LCMS showed product formed. After cooling, the mixture wasdiluted with EA, washed with brine, and dried over Na₂SO₄. Afterfiltration, the filtrate was concentrated. The crude material waspurified by flash column to yield the title compound. LC-MS calculatedfor C₃₇H₃₇Cl₂N₄O₅ (M+H)⁺: m/z=687.2; found 687.2.

Step 8:1-((7-chloro-2-(2′-chloro-3′-((5-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-3-methylpyrazin-2-yloxy)methyl)-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of tert-butyl1-((7-chloro-2-(2′-chloro-3′-(((5-formyl-3-methylpyrazin-2-yl)oxy)methyl)-2-methyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylate(10 mg, 0.015 mmol) and (S)-(−)-3-pyrrolidinol (3.80 mg, 0.044 mmol) inDCM (1 ml) was stirred at r.t. for 1 h. Then to the mixture was addedsodium triacetoxyborohydride (9.25 mg, 0.044 mmol). It was then stirredat r.t. for 2 hours. After quenching with water, the reaction wasextracted with DCM. The combined extracts were concentrated. The residuewas redissolved in DCM (1 ml). To the solution was added trifluoroaceticacid (0.7 ml, 9.09 mmol). The mixture was stirred at r.t. for 1 h. Afterconcentration, the reaction was diluted with MeOH and then purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₃₇H₃₈Cl₂N₅O₅ (M+H)⁺: m/z=702.2; found702.2.

Example 1541-((2-(2′-chloro-2-methyl-3′-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylicAcid

To a solution of tert-butyl2-(2-chloro-3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(Example 92, Step 3: 40 mg, 0.061 mmol) in DCM (2 mL) was addedpiperidine-4-carboxylic acid (11.9 mg, 0.092 mmol) and TEA (17.1 μl,0.123 mmol). The mixture was stirred at r.t. for 60 min. Then sodiumtriacetoxyborohydride (19.5 mg, 0.092 mmol) was added. The resultingmixture was stirred at r.t. overnight before 1 mL of TFA was added. Thereaction mixture was further stirred for 1 h. The reaction mixture wasthen concentrated and purified via prep-HPLC (pH=2, MeCN/water with TFA)to give the desired product as the TFA salt. LC-MS calculated forC₃₆H₃₅ClN₇O₄ (M+H)⁺: m/z=664.2; found 664.2.

Example 155(R)-1-((2-(2′-chloro-3′-(5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylicAcid

A solution of1-((2-(2′-chloro-2-methyl-3′-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylicacid, 3TFA (Example 154:20 mg, 20 μmol),(R)-2-((tert-butyldimethylsilyl)oxy)propanal (11.6 mg, 0.062 mmol) andHünig's base (10.8 μL, 0.062 mmol) in THF (0.5 mL) was stirred at roomtemperature for 1 h. Sodium triacetoxyborohydride (13.0 mg, 0.062 mmol)was added. After being stirred at room temperature for 2 h, 2 N HClaqueous solution (0.2 mL) was added, and the reaction was stirred at 50°C. for 30 min. The reaction mixture was diluted with acetonitrile, andpurified via pH 2 preparative HPLC (MeCN/water with TFA) to give thedesired product as TFA salt. LC-MS calculated for C₃₉H₄₁ClN₇O₅ (M+H)⁺:m/z=722.3; found 722.3.

TABLE 1 The compounds in Table 1 were prepared in accordance with thesynthetic protocols set forth in Example 154 and 155, using theappropriate starting materials. Ex. LCMS No. Name/¹HNMR Structure [M +H] 156 1-((2-(2′-chloro-3′-(5-(2- hydroxyethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5- c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyano- benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid

708.3 157 (R)-1-((2-(2′-chloro-3′-(5-((R)-2-hydroxypropyl)-1-methyl-4,5,6,7- tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2- methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3- methylpyrrolidine-3-carboxylic acid¹H NMR (600 MHz, DMSO) δ 9.97 (s, 1H), 8.41 (s, 1H), 8.29 (s, 1H), 8.23(d, J = 9.1 Hz, 1H), 8.15 (s, 1H), 7.61 (t, J = 1.8 Hz, 1H), 7.55 (t, J= 1.8 Hz, 1H), 7.50 (dd, J = 6.6, 1.2 Hz, 1H), 7.22 (dd, J = 7.2, 1.8Hz, 1H), 5.53 (br, s, 1H), 4.59 (br, s, 2H), 4.52-4.26 (m, 2H), 4.18(br, s, 1H),

722.3 3.96 (s, 3H), 3.94-2.96 (m, 10H), 2.54-2.48 (s, 3H), 2.03-1.86 (m,2H), 1.41-1.34 (m, 3H), 1.15 (d, J = 6 Hz, 3H).

Example 158(R)-1-((2-(2′-chloro-3′-(1,5-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic Acid

Step 1:(R)-1-((2-(2′-chloro-2-methyl-3′-(1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamido)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicAcid

To a solution of tert-butyl2-(2-chloro-3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate(Example 94, Step 6: 20 mg, 0.031 mmol) in DCM (1 mL) was added(R)-3-methyl pyrrolidine-3-carboxylic acid (8.0 mg, 0.062 mmol) and TEA(17.13 μl, 0.123 mmol). The mixture was stirred at r.t. for 60 min, thensodium triacetoxyborohydride (19.5 mg, 0.092 mmol) was added. Theresulting mixture was stirred at r.t. overnight before 1 mL of TFA wasadded. The reaction mixture was further stirred for 1 h. The reactionmixture was then quenched with sat. NaHCO₃ and extracted withchloroform/isopropanol (3/1 volume ratio). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentratedthen used in next step without further purification. LC-MS calculatedfor C₃₅H₃₃ClN₇O₄ (M+H)⁺: m/z=650.2; found 650.2.

Step 2:(R)-1-((2-(2′-chloro-3′-(1,5-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicAcid

Sodium triacetoxyborohydride (12.7 mg, 0.06 mmol) was added to asolution of(R)-1-((2-(2′-chloro-2-methyl-3′-(1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamido)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid (10 mg, 0.015 mmol) and 37 wt. % formaldehyde in water (4.5 μL,0.06 mmol) in DCM (0.5 mL). The reaction mixture was stirred at roomtemperature for 1 h, then concentrated and purified via pH 2 preparativeHPLC (MeCN/water with TFA) to give the desired product as TFA salt.LC-MS calculated for C₃₆H₃₅ClN₇O₄ (M+H)⁺: m/z=664.2; found 664.2.

Example 159(3R)-1-((2-(2′-chloro-3′-(1,6-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: tert-butyl6-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

To a stirred solution of (R)-1-(1H-imidazol-5-yl)propan-2-amine HCl salt(J&W PharmLab, Cat #40R0144: 500 mg, 2.94 mmol) in ethanol (5.0 ml) andwater (5.0 mL) was added formaldehyde (37 wt. % in water, 0.36 mL). Theresulted mixture was heated to reflux for 4 hrs. The reaction wasconcentrated under reduced pressure. The residue was dissolved in DCM(10 mL) and MeOH (10 mL). Di-tert-butyl dicarbonate (2.2 g, 10.21 mmol)and triethylamine (1.56 mL, 11.23 mmol) were added, and the resultingsolution was stirred at rt. for 1 hr before concentrated under reducedpressure. The residue was then dissolved in 7N NH₃ in MeOH and heated at70° C. for 6 hrs. The reaction was finally concentrated under reducedpressure and purified by flash chromatography on a silica gel columneluting with 0 to 20% MeOH in DCM to afford the racemic product. LC-MScalculated for C₁₂H₂₀N₃O₂ (M+H)⁺: m/z=238.2; found 238.2.

Step 2: tert-butyl1,6-dimethyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

Potassium bis(trimethylsilyl)amide (1.0 M in THF, 1.01 mL) was added toa solution of tert-butyl6-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (200mg, 0.843 mmol) in THF (4.2 mL) at −20° C. After stirring for 30 min,methyl iodide (63.2 μl, 1.011 mmol) was added and the mixture wasallowed to warm slowly to r.t. The mixture was continued to stir at thistemperature for 1 h. The reaction mixture was then quenched with sat.NaHCO₃ solution and extracted with DCM. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated and usedin next step without further purification. LC-MS calculated forC₁₃H₂₂N₃O₂ (M+H)⁺: m/z=252.2; found 252.2.

Step 3: 5-tert-butyl 2-methyl1,6-dimethyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-2,5(4H)-dicarboxylate

n-Butyl lithium (2.5 M in hexanes, 522 μl) was added to a cold (−78° C.)solution oftert-butyl-1,6-dimethyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate(210 mg, 0.836 mmol) in THF (6 mL). The reaction mixture was stirred at−78° C. for 10 min prior to the addition of methyl chloroformate (162μL, 2.09 mmol). After being stirred at −78° C. for 30 min, the reactionwas then quenched with saturated aqueous NaHCO₃ solution, and extractedwith ethyl acetate, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by flash chromatography on asilica gel column eluting with 100% ethyl acetate in hexanes to affordthe desired product. LC-MS calculated for C₁₅H₂₄N₃O₄ (M+H)⁺: m/z=310.2;found 310.2.

Step 4: tert-butyl2-(3-bromo-2-chlorophenylcarbamoyl)-1,6-dimethyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

Potassium tert-butoxide (1.0 M in THF, 0.36 mL) was added to a solutionof 5-(tert-butyl)2-methyl-1,6-dimethyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-dicarboxylate(56.0 mg, 0.181 mmol) and 3-bromo-2-chloroaniline (44.8 mg, 0.217 mmol)in tetrahydrofuran (6.0 mL). After being stirred at room temperature for1 hr, the reaction mixture was quenched with water, and extracted withethyl acetate. The combined organic layers were washed with brine, driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel columneluting with 50% ethyl acetate in hexanes to afford the desired product.LCMS calculated for C₂₀H₂₅BrClN₄O₃ (M+H)⁺: m/z=483.1; found 483.1.

Step 5: tert-butyl2-(2-chloro-3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1,6-dimethyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

A mixture oftert-butyl-2-((3-bromo-2-chlorophenyl)carbamoyl)-1,6-dimethyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate(78 mg, 0.161 mmol),5-(hydroxymethyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile(Example 54, Step 2: 70.0 mg, 0.18 mmol), anddichloro[1,1′-bis(dicyclohexyl phosphino)ferrocene]palladium(II) (13 mg,0.002 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was added cesiumcarbonate (38 mg, 0.36 mmol). The reaction mixture was purged withnitrogen and then stirred at 100° C. for 12 hrs. After being cooled toroom temperature, the reaction mixture was extracted with ethyl acetate.The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column eluting with 0to 100% EtOAc in hexanes to afford the desired product. LC-MS calculatedfor C₃₆H₃₆ClN₆O₅ (M+H)⁺: m/z=667.2; found 667.2.

Step 6: tert-butyl2-(2-chloro-3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1,6-dimethyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

To a stirred solution of tert-butyl2-(2-chloro-3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1,6-dimethyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(50 mg, 0.11 mmol) in DCM (5.0 ml) was added MnO₂ (215 mg, 2.5 mmol).The resulted mixture was stirred at 45° C. for 2 hrs, then filtered. Thefiltrate was concentrated under reduced pressure. The residue was usedin the next step directly without further purification. LC-MS calculatedfor C₃₆H₃₄ClN₆O₅ (M+H)⁺: m/z=665.2; found 665.2.

Step 7:(3R)-1-((2-(2′-chloro-3′-(1,6-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

To a solution of tert-butyl2-(2-chloro-3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1,6-dimethyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(12 mg, 0.015 mmol) in DCM (0.5 mL) was added(R)-pyrrolidine-3-carboxylic acid (4.0 mg, 0.032 mmol) and TEA (8.6 μl,0.07 mmol). The mixture was stirred at r.t. for 60 min. Sodiumtriacetoxyborohydride (9.8 mg, 0.046 mmol) was then added. The resultingmixture was stirred at r.t. overnight before 1 mL of TFA was added. Thereaction mixture was further stirred for 1 hr and concentrated underreduced pressure. The residue was dissolved in MeOH, and purified via pH2 preparative HPLC (MeCN/water with TFA) to give the desired product asTFA salt. LC-MS calculated for C₃₆H₃₅ClN₇O₄ (M+H)⁺: m/z=664.2; found664.2.

Example 160(3R)-1-((2-(2′-chloro-2-methyl-3′-(1,5,6-trimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Sodium triacetoxyborohydride (11.2 mg, 0.05 mmol) was added to asolution of(3R)-1-((2-(2′-chloro-3′-(1,6-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (Example 159, Step 7: 10 mg, 0.015 mmol) and 37 wt. % formaldehydein water (4.5 μL, 0.06 mmol) in DCM (0.5 mL). The reaction mixture wasstirred at room temperature for 1 h, then concentrated and purified viapH 2 preparative HPLC (MeCN/water with TFA) to give the desired productas TFA salt. LC-MS calculated for C₃₇H₃₇ClN₇O₄ (M+H)⁺: m/z=678.2; found678.2.

TABLE 2 The compounds in Table 2 were prepared in accordance with thesynthetic protocols set forth in Example 159 and 160, using theappropriate starting materials. Ex. LCMS No. Name Structure [M + H] 161(3R)-1-((2-(2′-chloro-2-methyl-3′- (1,5,6-trimethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5- c]pyridine-2- carboxamido)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5- yl)methyl)-3-methylpyrrolidine- 3-carboxylic acid

692.2 162 1-((2-(2′-chloro-2-methyl-3′- (1,5,6-trimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5- c]pyridine-2- carboxamido)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5- yl)methyl) piperidine-4- carboxylic acid

692.2 163 (3R)-1-((2-(2′-chloro-3′-(1,6- dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2- carboxamido)-2-methyl biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5- yl)methyl)-3-methylpyrrolidine-3-carboxylic acid

678.3 164 1-((2-(2′-chloro-3′-(1,6-dimethyl- 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2- carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5- yl)methyl) piperidine-4- carboxylic acid

678.3

Example 1652-(2-chloro-3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1,5,6-trimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylicAcid

Step 1: 5-tert-butyl 6-methyl1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5,6(4H)-dicarboxylate

To a stirred solution of(S)-2-amino-3-(1-methyl-1H-imidazol-5-yl)propanoic acid (500 mg, 2.06mmol) in ethanol (5.0 ml) and water (5.0 mL) was added formaldehyde (37wt. % in water, 0.36 ml). The resulted mixture was heated to reflux for4 h. The reaction was concentrated under reduced pressure. The residuewas dissolved MeOH (10 mL), and SOCl₂ (0.40 ml, 5.5 mmol) was slowlyadded to the above solution at 0° C. After addition, the resultingmixture was heated to reflux for 12 hrs before quenched with sat. NaHCO₃solution. The mixture was then extracted with extracted withchloroform/isopropanol (3:1 volume ratio). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was then dissolved in DCM (10 mL),followed by adding di-tert-butyl dicarbonate (1.2 g, 5.52 mmol) andtriethylamine (0.77 mL, 5.52 mmol). The resulting solution was stirredat rt. for 1 hr before concentrated and purified by flash chromatographyon a silica gel column eluting with 0 to 100% EtOAc in hexanes to affordthe racemic product. LC-MS calculated for C₁₄H₂₂N₃O₄ (M+H)⁺: m/z=296.2;found 296.2.

Step 2: 5-tert-butyl 6-methyl1,6-dimethyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5,6(4H)-dicarboxylate

Potassium bis(trimethylsilyl)amide (1.0 M in THF, 0.37 mL, 0.37 mmol)was added to a solution of 5-tert-butyl 6-methyl1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5,6(4H)-dicarboxylate(110 mg, 0.37 mmol) in THF (4 mL) at −20° C. After stirring for 30 min,methyl iodide (35 μl, 0.56 mmol) was added and the mixture was allowedto warm slowly to r.t. The reaction was continued to stir at thistemperature for 1 h. The reaction mixture was then quenched with sat.NaHCO₃ aqueous solution and extracted with DCM. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated and used in next step without further purification. LC-MScalculated for C₁₅H₂₄N₃O₄ (M+H)⁺: m/z=310.2; found 310.2.

Step 3: 5-tert-butyl 2,6-dimethyl1,6-dimethyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-2,5,6(4H)-tricarboxylate

LDA (1.0 M in THF, 550 μl) was added to a cold (−78° C.) solution of5-tert-butyl 6-methyl1,6-dimethyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5,6(4H)-dicarboxylate(170 mg, 0.55 mmol) in tetrahydrofuran (4 mL). The reaction mixture wasstirred at −78° C. for 20 min prior to the addition of methylchloroformate (106 μL, 1.37 mmol). After being stirred at −78° C. for 30min, the reaction was then quenched with saturated aqueous NaHCO₃solution, and extracted with ethyl acetate, dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified byflash chromatography on a silica gel column eluting with 100% ethylacetate in hexanes to afford the desired product. LC-MS calculated forC₁₇H₂₆N₃O₆ (M+H)⁺: m/z=368.2; found 368.2.

Step 4: 5-tert-butyl 6-methyl2-(3-bromo-2-chlorophenylcarbamoyl)-1,6-dimethyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5,6(4H)-dicarboxylate

Potassium tert-butoxide (1.0 M in THF, 0.653 ml) was added to a solutionof 5-tert-butyl 2,6-dimethyl1,6-dimethyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-2,5,6(4H)-tricarboxylate(120 mg, 0.327 mmol) and 3-bromo-2-chloroaniline (101 mg, 0.490 mmol) intetrahydrofuran (6.0 mL). After being stirred at room temperature for 1h, the reaction mixture was quenched with water, and extracted withethyl acetate. The combined organic layers were washed with brine, driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel columneluting with 0 to 100% ethyl acetate in hexanes to afford the desiredproduct. LCMS calculated for C₂₂H₂₇BrClN₄O₅ (M+H)⁺: m/z=541.1; found541.1.

Step 5:2-(3-bromo-2-chlorophenylcarbamoyl)-1,5,6-trimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylicAcid

A DCM (1 mL) solution of 5-tert-butyl 6-methyl2-(3-bromo-2-chlorophenylcarbamoyl)-1,6-dimethyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5,6(4H)-dicarboxylate(40 mg, 0.074 mmol) was added TFA (1 mL). The resulting mixture wasstirred at r.t. for 1 h before concentrated under reduced pressure. Theresidue was then dissolved in dry DCM, triethylamine (20.6 μl, 0.148mmol), 37 wt. % formaldehyde in water (11.0 μl, 0.148 mmol) and sodiumtriacetoxyborohydride (31.3 mg, 0.148 mmol) were added subsequently. Theresulting mixture was stirred for another 1 hr before quenched with sat.NaHCO₃ solution. The mixture was then extracted with extracted withchloroform/isopropanol (3:1 volume ratio). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was then dissolved in THF/MeOH/water(1:1:1 volume ratio), LiOH (8.8 mg, 0.37 mmol) was added and thereaction was stirred at 70° C. for 5 hrs. After completion, the reactionwas neutralized with 1N HCl solution and extracted withchloroform/isopropanol (3:1 volume ratio). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The crude product was used in the next reactionwithout further purification. LCMS calculated for C₁₇H₁₉BrClN₄O₃ (M+H)⁺:m/z=441.1; found 441.1.

Step 6:2-(2-chloro-3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1,5,6-trimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylicAcid

To a mixture of(R)-5-((3-hydroxypyrrolidin-1-yl)methyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile(Example 131, Step 4: 15.0 mg, 0.033 mmol),2-((3-bromo-2-chlorophenyl)carbamoyl)-1,5,6-trimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylicacid (12.0 mg, 0.027 mmol), anddichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II) (2.1 mg,0.003 mmol) in 1,4-dioxane (1 mL) and water (0.2 mL) was added sodiumcarbonate (6 mg, 0.054 mmol). The reaction mixture was purged withnitrogen and then stirred at 100° C. for 12 hrs. After being cooled toroom temperature, the reaction mixture was extracted with ethyl acetate.The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue wasdissolved in MeOH, and purified via pH 2 preparative HPLC (MeCN/waterwith TFA) to give the desired product as TFA salt. LC-MS calculated forC₃₇H₃₇ClN₇O₅ (M+H)⁺: m/z=694.2; found 694.2.

Example 166(R)-1-((7-cyano-2-(3′-(3-(4,5-dihydro-1H-imidazol-2-yl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:N-(3-bromo-2-methylphenyl)-3-(4,5-dihydro-1H-imidazol-2-yl)-1,7-naphthyridin-8-amine

To a suspension of8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde(Example 16, Step 3: 146 mg, 0.427 mmol) in tert-butanol (4.3 ml) wasadded ethane-1,2-diamine (28.2 mg, 0.469 mmol). The mixture was stirredat r.t. under N₂ atmosphere for 30 min, and then hypochlorous acidtert-butyl ester (57.7 μl, 0.512 mmol) was added, and the mixture wasstirred at 50° C. After 2 h, the mixture was quenched with sat. aqNa₂SO₃ (10 mL) and was extracted with DCM (3×10 mL). The organic layerwas washed with sat. aq Na₂CO₃ and brine, and dried over Na₂SO₄. Afterfiltration, the mixture was evaporated. The product was purified byflash column chromatography. LCMS calculated for C₁₈H₁₇BrN₅ (M+H)+:m/z=382.1, 384.1; found 382.1, 384.1.

Step 2:2-(3′-(3-(4,5-dihydro-1H-imidazol-2-yl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile

A mixture ofN-(3-bromo-2-methylphenyl)-3-(4,5-dihydro-1H-imidazol-2-yl)-1,7-naphthyridin-8-amine(26 mg, 0.068 mmol),5-formyl-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile(Example 138, Step 1: 34 mg, 0.088 mmol),tetrakis(triphenylphosphine)palladium(0) (7.86 mg, 6.80 μmol) and sodiumcarbonate (18.0 mg, 0.170 mmol) in water (76 μl) and dioxane (378 μl)was purged with N₂ and then stirred at 100° C. for 5 h. The reaction wascooled to room temperature. The reaction mixture was diluted with DCMand H₂O. The layers were separated. The aqueous layer was extracted withDCM three times. The organic layer was dried over MgSO₄, filtered andconcentrated to give a crude residue, which was purified by flashchromatography on a silica gel column eluting with 0 to 14% MeOH/DCM togive the desired product. LC-MS calculated for C₃₄H₂₆N₇O₂ (M+H)⁺:m/z=564.2; found 564.2.

Step 3:(R)-1-((7-cyano-2-(3′-(3-(4,5-dihydro-1H-imidazol-2-yl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedure as described in Step5, Example 24 with2-(3′-(3-(4,5-dihydro-1H-imidazol-2-yl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrilereplacing(R)-5-formyl-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile.The reaction was diluted with MeOH and then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₃₉H₃₅N₈O₃ (M+H)⁺: m/z=663.3; found 663.3.

Example 167(R)-1-((7-cyano-2-(3′-(3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:2-(8-(3-bromo-2-methylphenylamino)-1,7-naphthyridin-3-yl)acetaldehyde

(methoxymethyl)triphenylphosphonium chloride (Aldrich #309567: 145 mg,0.422 mmol) was dissolved in dry THF (1622 μl) under nitrogen. Thissolution was cooled at 0° C. and potassium tert-butoxide (1.0 M in THF,389 μl) was added. The reaction mixture was stirred at 0° C. for 30 min.A solution of8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde (111mg, 0.324 mmol) in dry THF was added, then the reaction mixture waswarmed up to r.t. and stirred for 1 hour. The solvent was removed underreduced pressure, the residue was taken with ethyl acetate, stirred,filtered and the solid cake washed with ethyl acetate (2 times). Thefiltrate was evaporated under reduced pressure. To the above residue andsodium iodide (72.9 mg, 0.487 mmol) in acetonitrile (1.6 ml) was addedchlorotrimethylsilane (52.9 mg, 0.487 mmol). The mixture was stirred atr.t. for 2 h. The mixture was then filtered to remove the insoluble. Thefiltrate was concentrated and the residue was used directly in next stepwithout further purification. LC-MS calculated for C₁₇H₁₅BrN₃O (M+H)⁺:m/z=356.0, 358.0; found 356.2, 358.1.

Step 2:(R)-1-(2-(8-(3-bromo-2-methylphenylamino)-1,7-naphthyridin-3-yl)ethyl)pyrrolidin-3-ol

This compound was prepared using similar procedure as described in Step1, Example 24 with2-(8-(3-bromo-2-methylphenylamino)-1,7-naphthyridin-3-yl)acetaldehydereplacing8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde. Thecrude material was purified by column chromatography. LC-MS calculatedfor C₂₁H₂₄BrN₄O (M+H)⁺: m/z=427.1, 429.1; found 427.3, 429.3.

Step 3:(R)-1-((7-cyano-2-(3′-(3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of(R)-1-(2-(8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)ethyl)pyrrolidin-3-ol(15 mg, 0.035 mmol),(R)-1-((7-cyano-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (Example 126, Step 5: 18.82 mg, 0.039 mmol), sodium carbonate (9.30mg, 0.088 mmol) and 1,1′-bis(di-cyclohexylphosphino)ferrocene palladiumdichloride (2.6 mg, 3.5 μmol) in water (58 μl) and 1,4-dioxane (293 μl)was purged with N₂ and then stirred at 100° C. for 1 h. The reaction wascooled to room temperature. The reaction was concentrated, then dilutedin MeOH, filtered then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₄₂H₄₂N₇O₄ (M+H)⁺: m/z=708.3; found 708.3.

Example 168(R)-1-((2-(2-chloro-3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2′-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:2-chloro-3-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)phenylboronicAcid

A mixture of 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(178 mg, 0.702 mmol),(2-(3-bromo-2-chlorophenyl)-7-chlorobenzo[d]oxazol-5-yl)methanol(Example 69, Step 3: 238 mg, 0.638 mmol), potassium acetate (157 mg,1.595 mmol) and1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (52 mg, 0.064 mmol) in dioxane (4.2 ml) waspurged with N₂ and then stirred at 90° C. for 3 h. The reaction was thencooled to r.t. The mixture was diluted with DCM, filtered through ashort pad of Celite. The filtrate was concentrated and purified bycolumn chromatography. LC-MS calculated for C₁₄H₁₁BCl₂NO₄ (M+H)⁺:m/z=338.0; found 338.0.

Step 2:(R)-1-((2-(2-chloro-3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2′-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedure as described in Step2-5, Example 24 with2-chloro-3-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)phenylboronicacid replacing(7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanolin Step 2. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₄₀H₃₇ClN₇O₄ (M+H)⁺: m/z=714.3; found 714.3.

TABLE 3 The compounds in Table 3 were prepared in accordance with thesynthetic protocols set forth in Example 24, using the appropriateamines for reductive amination in last step. Ex. LCMS No. Name Structure[M + H] 169 (1R,3S)-3-((7-cyano-2-(3′-(3- (((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8- ylamino)-2,2′-dimethyl-biphenyl-3-yl)benzo[d]oxazol- 5-yl) methylamino)cyclopentane- carboxylicacid

708.3 170 (1S,3R)-3-((7-cyano-2-(3′-(3- (((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8- ylamino)-2,2′-dimethyl-biphenyl-3-yl)benzo[d]oxazol- 5-yl) methylamino)cyclopentane- carboxylicacid

708.3 171 (R)-4-(2-((7-cyano-2-(3′-(3- ((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin- 8-ylamino)-2,2′- dimethylbiphenyl-3-yl)benzo[d]oxazol-5- yl)methylamino)ethyl)benzoic

744.3 acid 172 cis-4-((7-cyano-2-(3′-(3-(((R)- 3-hydroxy pyrrolidin-1-yl)methyl)-1,7-naphthyridin- 8-ylamino)-2,2′- dimethylbiphenyl-3-yl)benzo[d]oxazol-5- yl)methylamino) cyclohexanecarboxylic acid

722.6 173 2-((R)-1-((7-cyano-2-(3′-(3- (((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8- ylamino)-2,2′- dimethylbiphenyl-3-yl)benzo[d]oxazol-5- yl)methyl)pyrrolidin-3-

708.5 yl)acetic acid 174 2-((S)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1- yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′- dimethylbiphenyl-3- yl)benzo[d]oxazol-5-yl)methyl)pyrrolidin-3-

708.5 yl)acetic acid 175 (1R,2S)-2-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1- yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethyl- biphenyl-3-yl)benzo[d]oxazol- 5-yl) methylamino)cyclopentanecarboxylic acid

708.3 176 2-((7-cyano-2-(3′-(3-(((R)-3- hydroxy pyrrolidin-1-yl)methyl)-1,7-naphthyridin- 8-ylamino)-2,2′- dimethylbiphenyl-3-yl)benzo[d]oxazol-5- yl)methyl)-2-aza-

720.3 bicyclo[2.2.1]heptane-5- carboxylic acid 1772-((7-cyano-2-(3′-(3-(((R)-3- hydroxy pyrrolidin-1-yl)methyl)-1,7-naphthyridin- 8-ylamino)-2,2′- dimethylbiphenyl-3-yl)benzo[d]oxazol-5- yl)methyl)-2-

720.3 azaspiro[3.3]heptane-6- carboxylic acid 178(R)-2-((7-cyano-2-(3′-(3-((3- hydroxy pyrrolidin-1-yl)methyl)-1,7-naphthyridin- 8-ylamino)-2,2′- dimethylbiphenyl-3-yl)benzo[d]oxazol-5- yl)methyl)-2-aza-

706.3 bicyclo[2.1.1]hexane-4- carboxylic acid 179(1S,2S)-2-((7-cyano-2-(3′-(3- (((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8- ylamino)-2,2′-dimethyl-biphenyl-3-yl)benzo[d]oxazol- 5-yl) methylamino)cyclopentane- carboxylicacid

708.6

TABLE 4 The compounds in Table 4 were prepared in accordance with thesynthetic protocols set forth in Example 24, using the appropriate aminoesters for reductive amination followed by saponification. Ex. LCMS No.Name Structure [M + H] 180 cis-3-((7-cyano-2-(3′-(3- (((R)-3-hydroxypyrrolidin- 1-yl)methyl)-1,7- naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3- yl)benzo [d]oxazol-5- yl)methylamino)cyclobutane carboxylic acid

694.5 181 trans-3-((7-cyano-2-(3′-(3- (((R)-3-hydroxy pyrrolidin-1-yl)methyl)-1,7- naphthyridin-8-ylamino)- 2,2′-dimethylbiphenyl-3-yl)benzo [d]oxazol-5- yl)methylamino)cyclobutane carboxylic acid

694.5 182 (1S,3S)-3-((7-cyano-2-(3′- (3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)- 1,7-naphthyridin-8- ylamino)-2,2′-dimethylbiphenyl-3- yl)benzo [d]oxazol-5- yl)methylamino) cyclopentanecarboxylic acid

708.5 183 (R)-4-(7-cyano-2-(3′-(3- ((3-hydroxy pyrrolidin-1-yl)methyl)-1,7- naphthyridin-8-ylamino)- 2,2′-dimethylbiphenyl-3-yl)benzo [d]oxazol-5- yl)methylamino)bicyclo [2.2.1]heptane-1-

734.5 carboxylic acid 184 2-(trans-4-((7-cyano-2-(3′- (3-(((R)-3-hydroxypyrrolidin-1- yl)methyl)-1,7- naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3- yl)benzo[d]oxazol-5-

736.5 yl)methylamino)cyclohexyl) acetic acid

TABLE 5 The compounds in Table 5 were prepared in accordance with thesynthetic protocols set forth in Example 24, using the appropriate aminotert-butyl esters for reductive amination followed by treatment of TFAin DCM to remove the tert-butyl groups. Ex. LCMS No. Name Structure [M +H] 185 1-((7-cyano-2-(3′-(3-(((R)- 3-hydroxy pyrrolidin-1-yl)methyl)-1,7-naphthyridin- 8-ylamino)-2,2′- dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)

738.5 methyl)-3-(methoxy methyl)pyrrolidine-3- carboxylic acid 186(R)-1-((7-cyano-2-(3′-(3- ((3-hydroxy pyrrolidin-1-yl)methyl)-1,7-naphthyridin- 8-ylamino)-2,2′- dimethylbiphenyl-3-yl)benzo[d]oxazol-5-

708.3 yl)methyl)piperidine-4- carboxylic acid

TABLE 6 The compounds in Table 6 were prepared in accordance with thesynthetic protocols set forth in Example 30, using the appropriatestarting material (R)-pyrrolidin-3-ol and different amino acids. Ex.LCMS No. Name Structure [M + H] 187 (R)-1-((2-(2′-chloro-3′-(3-(((R)-3-hydroxy pyrrolidin-1-yl)methyl)- 1,7-naphthyridin-8-ylamino)-2-methyl- biphenyl-3-yl)-7-

728.2 cyanobenzo[d]oxazol- 5-yl)methyl)-3- methylpyrrolidine-3-carboxylic acid 188 (R)-1-((2-(2′-chloro-3′- (3-((3-hydroxypyrrolidin-1-yl) methyl)-1,7-naphthyridin- 8-ylamino)-2-methyl-biphenyl-3-yl)-7-

728.2 cyanobenzo[d]oxazol- 5-yl)methyl) piperidine- 4-carboxylic acid

Example 189(R)-1-((7-cyano-2-(3′-(3-((2-hydroxyethylamino)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicAcid

Step 1:(R)-1-((7-cyano-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedure as described inExample 138, Step 2 with (R)-3-methylpyrrolidine-3-carboxylic acidreplacing (R)-pyrrolidine-3-carboxylic acid. LC-MS calculated forC₂₈H₃₃BN₃O₅ (M+H)⁺: m/z=502.2; found 502.2.

Step 2:(R)-1-((7-cyano-2-(3′-(3-formyl-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicAcid

A mixture of8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde(Example 16, Step 3: 278 mg, 0.812 mmol),(R)-1-((7-cyano-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid (370 mg, 0.738 mmol), tetrakis(triphenylphosphine)palladium(0) (85mg, 0.074 mmol) and potassium phosphate (392 mg, 1.845 mmol) in water(820 μl) and dioxane (4100 μl) was purged with N₂ and then stirred at100° C. for 3 h. The reaction was cooled to room temperature. Thereaction mixture was diluted with DCM and H₂O. The layers wereseparated. The aqueous layer was extracted with DCM three times. Theorganic layer was dried over MgSO₄, filtered and concentrated to give acrude residue, which was purified by flash chromatography on a silicagel column eluting with 0 to 14% MeOH/DCM to give the desired product.LC-MS calculated for C₃₈H₃₃N₆O₄ (M+H)⁺: m/z=637.3; found 637.3.

Step 3:(R)-1-((7-cyano-2-(3′-(3-((2-hydroxyethylamino)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo-[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicAcid

A mixture of(R)-1-((7-cyano-2-(3′-((3-formyl-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid (9.5 mg, 0.015 mmol) and 2-aminoethan-C-ol (1.367 mg, 0.022 mmol)in DCM (0.15 ml) was stirred at mi for 2 h. Then sodiumtriacetoxyborohydride (6.32 mg, 0.030 mmol) were added. The mixture wasfurther stirred at r.t. for 1 h. The reaction was concentrated, thendiluted in MeOH, filtered then purified by prep-HPLC (pH=10,acetonitrile/water+NH₄OH) to give the desired product. LC-MS calculatedfor C₄₀H₄₀N₇O₄ (M+H)⁺: m/z=682.3; found 682.2.

TABLE 7 The compounds in Table 7 were prepared in accordance with thesynthetic protocols set forth in Example 189, using the appropriatestarting materials. Ex. LCMS No. Name Structure [M + H] 190(R)-1-((7-cyano-2-(3′-(3- (((2-hydroxyethyl) (methyl)amino)methyl)-1,7-naphthyridin- 8-ylamino)-2,2′-dimethyl-biphenyl-3-yl)benzo[d] oxazol-5-yl)methyl)-3-

696.3 methylpyrrolidine- 3-carboxylic acid 191 (R)-1-((7-cyano-2-(3′-(3-(((S)-2-hydroxypropyl- amino)methyl)- 1,7-naphthyridin-8-yl-amino)-2,2′-dimethyl- biphenyl-3-yl)benzo [d]oxazol-5-yl)methyl)

696.3 3-methylpyrrolidine-3- carboxylic acid 192(R)-1-((7-cyano-2-(3′-(3- (((R)-2-hydroxypropyl- amino)methyl)-1,7-naphthyridin-8-ylamino)- 2,2′-dimethylbiphenyl-3- yl)benzo[d]oxazol-5-yl)methyl)-3-methyl-

696.3 pyrrolidine-3- carboxylic acid 193 (R)-1-(7-cyano-2-(2,2′-dimethyl-3′-(3- (pyrrolidin-1- ylmethyl)-1,7- naphthyridin-8-ylamino)biphenyl-3- yl)benzo[d]oxazol-5- yl)methyl)-3-methyl-

692.3 pyrrolidine-3- carboxylic acid 194 (R)-1-((7-cyano-2-(3′-(3-(((S)-1-hydroxybutan-2- ylamino)methyl)-1,7- naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3- yl)benzo[d]oxazol-5- yl)methyl)-3-methyl-pyrrolidine-3-

710.3 carboxylic acid 195 (R)-1-((7-cyano-2-(3′-(3-(((S)-1-hydroxypropan-2- ylamino)methyl)-1,7- naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3- yl)benzo[d]oxazol-5-yl) methyl)-3-methyl-

696.3 pyrrolidine-3- carboxylic acid 196 (R)-1-((7-cyano-2-(3′-(3-(((R)-1-hydroxy propan- 2-ylamino)methyl)-1,7- naphthyridin-8-ylamino)-2,2′-dimethyl biphenyl-3- yl)benzo[d]oxazol-5-yl) methyl)-3-methyl-

696.3 pyrrolidine-3- carboxylic acid 197 (R)-1-(7-cyano-2-(2,2′-dimethyl-3′-(3- ((methylamino)methyl)- 1,7-naphthyridin-8-ylamino)biphenyl-3- yl)benzo[d]oxazol-5-yl) methyl)-3-methylpyrrolidine-3-

652.2 carboxylic acid 198 (R)-1-((7-cyano-2-(3′- (3-((1-hydroxy-2-methylpropan-2- ylamino)methyl)-1,7- naphthyridin-8-ylamino)-2,2′-dimethyl biphenyl-3- yl)benzo[d]oxazol-5-yl)

710.3 methyl)-3-methyl- pyrrolidine-3- carboxylic acid 199(R)-1-((7-cyano-2-(3′-(3- (((1-hydroxycyclopropyl) methylamino)methyl)-1,7-naphthyridin-8- ylamino)-2,2′- dimethylbiphenyl-

708.3 3-yl)benzo[d]oxazol- 5-yl)methyl)-3-methyl- pyrrolidine-3-carboxylic acid 200 (R)-1-((7-cyano-2-(3′-(3- (((S)-3-hydroxy-3-methylpyrrolidin-1- yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethyl biphenyl-3-yl)benzo[d]

722.3 oxazol-5-yl)methyl)-3- methylpyrrolidine- 3-carboxylic acid

Example 201(S)-1-((7-cyano-2-(3′-(3-((1-hydroxypropan-2-ylamino)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylicAcid

Step 1: tert-butyl1-((7-cyano-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylate

This compound was prepared using similar procedure as described inExample 138, Step 2 with tert-butyl piperidine-4-carboxylate replacing(R)-pyrrolidine-3-carboxylic acid. LC-MS calculated for C₃₂H₄₁BN₃O₅(M+H)⁺: m/z=558.3; found 558.3.

Step 2: tert-butyl1-((7-cyano-2-(3′-(3-formyl-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylate

This compound was prepared using similar procedure as described inExample 189, Step 2 with tert-butyl1-((7-cyano-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylatereplacing(R)-1-((7-cyano-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid. LC-MS calculated for C₄₂H₄₁N₆O₄ (M+H)⁺: m/z=693.3; found 693.3.

Step 3:(S)-1-((7-cyano-2-(3′-(3-((1-hydroxypropan-2-ylamino)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylicAcid

A mixture of tert-butyl1-((7-cyano-2-(3′-(3-formyl-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylate (10.5mg, 0.015 mmol) and (S)-2-aminopropan-1-ol (1.7 mg, 0.023 mmol) in DCM(0.15 ml) was stirred at r.t. for 2 h. Then sodium triacetoxyborohydride(6.42 mg, 0.030 mmol) were added. The mixture was further stirred atr.t. for 1 h. Then trifluoroacetic acid (140 μl, 1.82 mmol) was added.The mixture was stirred at r.t. for 30 min. The reaction wasconcentrated, then diluted in MeOH, filtered then purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as TFA salt.LC-MS calculated for C₄₁H₄₂N₇O₄ (M+H)⁺: m/z=696.3; found 696.3.

TABLE 8 The compounds in Table 8 were prepared in accordance with thesynthetic protocols set forth in Example 201, using the appropriatestarting materials. Ex. LCMS No. Name Structure [M + H] 202(R)-1-((7-cyano-2-(3′-(3-((1- hydroxypropan-2- ylamino)methyl)-1,7-naphthyridin-8-ylamino)-2,2′- dimethyl biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl) piperidine-4-carboxylic acid

696.3 203 (R)-1-((7-cyano-2-(3′-(3-((2- hydroxypropyl amino)methyl)-1,7-naphthyridin-8-ylamino)-2,2′- dimethyl biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl) piperidine-4-carboxylic acid

696.3 204 (S)-1-(7-cyano-2-(3′-(3-((2- hydroxypropylamino)methyl)-1,7-naphthyridin-8-ylamino)- 2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5- yl)methyl)piperidine-4-

696.3 carboxylic acid

TABLE 9 The compounds in Table 9 were prepared in accordance with thesynthetic protocols set forth in Example 139, using the appropriatestarting materials. Ex. LCMS No. Name Structure [M + H] 205(R)-1-((7-cyano-2-(3′-(7- (((R)-3-hydroxypyrrolidin- 1-yl)methyl)pyrido[3,2- d]pyrimidin-4-ylamino)-2,2′- dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl) methyl)-3-methylpyrrolidine-

709.3 3-carboxylic acid 206 (S)-1-((7-cyano-2-(3′-(7-(((R)-3-hydroxypyrrolidin-1- yl)methyl)pyrido [3,2-d]pyrimidin-4-ylamino)-2,2′- dimethylbiphenyl-3- yl)benzo[d]oxazol-5-yl)methyl)piperidine-3-

709.3 carboxylic acid 207 (R)-1-((7-cyano-2-(3′-(7-((3-hydroxypyrrolidin-1- yl)methyl)pyrido [3,2- d]pyrimidin-4-ylamino)-2,2′-dimethylbiphenyl-3-yl) benzo[d]oxazol-5-

709.3 yl)methyl)piperidine-4- carboxylic acid ¹H NMR (500 MHz, DMSO) δ9.09 (s, 1H), 8.69 (s, 1H), 8.45 (d, J = 1.5 Hz, 1H), 8.36 (s, 1H), 8.19(d, J = 7.7 Hz, 1H), 8.10 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.59 (t, J= 7.7 Hz, 1H), 7.47 (d, J = 7.4 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.16(d, J = 7.3 Hz, 1H), 4.69 (br, s, 2H), 4.57-4.41 (m, 3H), 3.84-2.91 (m,8H), 2.57-2.51 (m, 1H), 2.47 (s, 3H), 2.36-1.66 (m, 6H), 1.98 (s, 3H).208 (R)-1-(7-cyano-2-(3′-(7-(((S)-2- hydroxypropylamino)methyl)pyrido[3,2-d]pyrimidin- 4-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5- yl)methyl)-3-methylpyrrolidine-3-carboxylic acid

697.3 209 (R)-1-((7-cyano-2-(2,2′- dimethyl-3′-(7-(pyrrolidin-1-ylmethyl)pyrido[3,2- d]pyrimidin-4- ylamino)biphenyl-3-yl)benzo[d]oxazol-5- yl)methyl)pyrrolidine-3-

679.3 carboxylic acid

Example 210(R)-1-((8-(3′-(7-cyano-5-(((S)-2-hydroxypropylamino)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:(R)-1-((8-(3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of(R)-1-((8-(3-bromo-2-methylphenylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylicacid (Example 141, Step 1: 333 mg, 0.755 mmol),5-formyl-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile(Example 138, Step 1: 293 mg, 0.755 mmol), potassium phosphate (400 mg,1.886 mmol) and tetrakis(triphenylphosphine) palladium(0) (87 mg, 0.075mmol) in water (838 μl) and dioxane (4192 μl) was purged with N₂ andthen stirred at 100° C. for 4 h. The reaction was cooled to roomtemperature. The reaction mixture was diluted with DCM/isopropanol (4:1)and H₂O. The layers were separated. The aqueous layer was extracted withDCM/isopropanol (4:1) three times. The organic layer was dried overMgSO₄, filtered and concentrated to give a crude residue, which waspurified by flash chromatography on a silica gel column eluting with 0to 15% MeOH/DCM to give the desired product. LC-MS calculated forC₃₇H₃₁N₆O₄ (M+H)⁺: m/z=623.2; found 623.2.

Step 2:(R)-1-((8-(3′-(7-cyano-5-(((S)-2-hydroxypropylamino)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylicAcid

A mixture of(R)-1-((8-(3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylicacid (11 mg, 0.018 mmol) and (S)-2-aminopropan-1-ol (2.0 mg, 0.026 mmol)in DCM (0.12 ml) was stirred at r.t. for 1 h. Then sodiumtriacetoxyborohydride (7.5 mg, 0.035 mmol) was added. The mixture wasfurther stirred at r.t. for 1 h. The reaction was concentrated, thendiluted in MeOH, filtered then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired TFA salt. LC-MS calculatedfor C₄₀H₄₀N₇O₄ (M+H)⁺: m/z=682.3; found 682.3.

TABLE 10 The compounds in Table 10 were prepared in accordance with thesynthetic protocols set forth in Example 210, using the appropriatestarting materials. Ex. LCMS No. Name Structure [M + H] 211(R)-1-((8-(3′-(7-cyano-5- (((S)-1-hydroxypropan-2- ylamino)methyl)benzo[d]oxazol-2-yl)-2,2′- dimethyl biphenyl-3-ylamino)-1,7-naphthyridin- 3-yl)methyl)pyrrolidine-3- carboxylic acid

682.3 212 (S)-1-((8-(3′-(7-cyano-5- ((2-hydroxypropylamino)methyl)benzo[d] oxazol-2-yl)-2,2′- dimethylbiphenyl-3-ylamino)-1,7- naphthyridin-

696.3 3-yl)methyl)piperidine- 4-carboxylic acid 213(S)-1-(8-(3′-(7-cyano-5- ((1-hydroxypropan-2- ylamino)methyl)benzo[d]oxazol-2-yl)-2,2′- dimethyl biphenyl-3- ylamino)-1,7-naphthyridin-3- yl)methyl)piperidine-4-

696.3 carboxylic acid 214 (R)-1-((8-(3′-(7-cyano-5-((3-hydroxypyrrolidin-1- yl)methyl) benzo[d]oxazol-2- yl)-2,2′-dimethylbiphenyl-3- ylamino)-1,7-naphthyridin-3- yl)methyl)piperidine-4-carboxylic acid

708.3 215 (R)-1-((8-(3′-(7-cyano-5- (((S)-1-hydroxypropan-2-ylamino)methyl) benzo[d]oxazol-2-yl)-2,2′- dimethyl biphenyl-3-ylamino)-1,7-naphthyridin- 3-yl)methyl)-3- methylpyrrolidine-3-

696.3 carboxylic acid 216 (R)-1-((8-(3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1- yl)methyl)benzo [d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3- ylamino)-1,7-naphthyridin- 3-yl)methyl)-3-

708.3 methylpyrrolidine-3- carboxylic acid

Example 217(R)-1-((7-cyano-2-(3′-(5-(2-(isopropyl(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicAcid

Step 1:2-(3′-(5-(2-chloroacetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile

To a stirred solution of2-(3′-(5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile(Example 105, Step 5: 100 mg, 0.210 mmol) in DCM (5.0 ml), Hunig's base(0.073 ml, 0.420 mmol) and 2-chloroacetyl chloride (28.4 mg, 0.252 mmol)were added sequentially at room temperature. After 1 hour, the reactionmixture was quenched with saturated aq. NaHCO₃, extracted with DCM (3×20mL). The organic layers were combined, dried over Na₂SO₄, filtered andthe filtrate was concentrated under reduced pressure. The residue waspurified by chromatography on silica gel, eluting with 0-60%EtOAc/hexanes, to give the desired product (102 mg). LC-MS calculatedfor C₃₀H₂₂ClN₄O₃S (M+H)⁺: m/z=553.1; found 553.1.

Step 2:5-formyl-2-(3′-(5-(2-(isopropyl(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile

To a stirred solution of2-(3′-(5-(2-chloroacetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile(40 mg, 0.072 mmol) in acetonitrile (1.0 ml), Hunig's base (0.025 ml,0.145 mmol) and N-methylpropan-2-amine (7.94 mg, 0.108 mmol) were addedsequentially at room temperature. After 6 h, the volatiles were removedand the residue was purified by chromatography on silica gel, elutingwith 0-15% MeOH/DCM, to give the desired product (36 mg). LC-MScalculated for C₃₄H₃₂N₅O₃S (M+H)⁺: m/z=590.2; found 590.2.

Step 3:(R)-1-((7-cyano-2-(3′-(5-(2-(isopropyl(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicAcid

To a stirred solution of5-formyl-2-(3′-(5-(2-(isopropyl(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile(5.0 mg, 8.90 μmol) and (R)-3-methylpyrrolidine-3-carboxylic acid (2.3mg, 0.018 mmol) in DMF (0.5 ml)/Water (0.2 ml), Hunig's base (4.7 μl,0.027 mmol) was added at room temperature. After 0.5 h, sodiumcyanoborohydride (1.7 mg, 0.027 mmol) was added and the resulted mixturewas stirred at room temperature overnight. The reaction mixture was thendiluted with MeOH, purified on prep LCMS (pH 2, acetonitrile/water+TFA)to give the desired product as its TFA salt. LC-MS calculated forC₄₀H₄₃N₆O₄S (M+H)⁺: m/z=703.3; found 703.3.

TABLE 11 The compounds in Table 11 were prepared in accordance with thesynthetic protocols set forth in Example 217, using the appropriatestarting materials. Ex. LCMS No. Name Structure [M + H] 218(R)-1-(7-cyano-2-(3′-(5- (2-(ethyl(methyl)amino) acetyl)-5,6-dihydro-4H-pyrrolo[3,4- d]thiazol-2-yl)-2,2′- dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl) methyl)- 3-methylpyrrolidine-3- carboxylic acid

689.3 219 (R)-1-(7-cyano-2-(3′-(5- (2-((cyclopropylmethyl)(methyl)amino)acetyl)- 5,6-dihydro-4H- pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3- yl)benzo[d]oxazol-5-yl) methyl)-3-methylpyrrolidine-3- carboxylic acid

715.3 220 2-((7-cyano-2-(3′-(5-(2- (ethyl(methyl)amino)acetyl)-5,6-dihydro-4H- pyrrolo[3,4- d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3- yl)benzo[d]oxazol-5- yl)methyl)-2-azabicyclo[2.1.1]hexane-4- carboxylic acid

687.3

Example 221(R)-1-((7-cyano-2-(3′-(5-(2-((S)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicAcid

Step 1:(R)-1-((2-(3′-(5-(2-chloroacetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicAcid

A solution of2-(3′-(5-(2-chloroacetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile(Example 217, Step 1: 100.0 mg, 0.181 mmol) and(R)-3-methylpyrrolidine-3-carboxylic acid (35.0 mg, 0.271 mmol) in DMF(3.0 ml) was stirred at room temperature for 30 min. Sodiumcyanoborohydride (22.7 mg, 0.262 mmol) was then added and the resultedmixture was stirred at room temperature overnight. The volatiles wereremoved under reduced pressure and the residue was purified bychromatography on silica gel, eluting with 0-15% MeOH/DCM, to give thedesired product (66 mg). LC-MS calculated for C₃₆H₃₃ClN₅O₄S (M+H)⁺:m/z=666.2; found 666.2.

Step 2:(R)-1-((7-cyano-2-(3′-(5-(2-((S)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicAcid

To a stirred solution of(R)-1-((2-(3′-(5-(2-chloroacetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid (10.0 mg, 0.015 mmol) in acetonitrile (1.0 mL), (S)-pyrrolidin-3-ol(1.962 mg, 0.023 mmol) and Hunig's base (7.87 μl, 0.045 mmol) were addedat room temperature. The resulted mixture was heated at 60° C. After 2h, the volatiles were removed under reduced pressure and the residue waspurified by purified on prep LCMS (pH 2, acetonitrile/water+TFA) to givethe desired product as its TFA salt. LC-MS calculated for C₄₀H₄₁N₆O₅S(M+H)⁺: m/z=717.3; found 717.3.

TABLE 12 The compounds in Table 12 were prepared in accordance with thesynthetic protocols set forth in Example 221, using the appropriatestarting materials. Ex. LCMS No. Name Structure [M + H] 222(R)-1-((7-cyano-2-(3′-(5- (2-((R)-3-hydroxy- pyrrolidin-1-yl)acetyl)-5,6-dihydro-4H- pyrrolo[3,4-d]thiazol-2- yl)-2,2′-dimethyl-biphenyl-3-yl)benzo [d]oxazol-5-yl) methyl)-3-methyl- pyrrolidine-3-carboxylic acid

717.3 223 (R)-1-((7-cyano-2-(3′- (5-(2-(4-ethylpiperazin- 1-yl)acetyl)-5,6- dihydro-4H-pyrrolo[3,4- d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3- yl)benzo[d]oxazol-5-yl) methyl)-3-methyl-pyrrolidine-3- carboxylic acid

744.3 224 (R)-1-((7-cyano-2-(3′- (5-(2-((2-hydroxyethyl) (methyl)amino)acetyl)-5,6-dihydro-4H- pyrrolo[3,4-d]thiazol-2- yl)-2,2′-dimethyl-biphenyl-3-yl)benzo [d]oxazol-5-yl)methyl)- 3-methylpyrrolidine-3-carboxylic acid

705.3 225 (R)-1-((7-cyano-2-(3′- (5-(2-(((R)-1-hydroxy-propan-2-yl)(methyl) amino)acetyl)- 5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′- dimethylbiphenyl-3- yl)benzo[d]oxazol-5-yl)methyl)- 3-methylpyrrolidine-3- carboxylic acid

719.3 226 (R)-1-((7-cyano-2-(3′-(5- (2-(((S)-1-hydroxypropan-2-yl)(methyl)amino) acetyl)-5,6- dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′- dimethylbiphenyl-3- yl)benzo[d]oxazol-5-yl)methyl)- 3-methylpyrrolidine-3- carboxylic acid

719.3 227 (R)-1-((7-cyano-2-(3′-(5- (2-(3-hydroxyazetidin-1-yl)acetyl)-5,6-dihydro- 4H-pyrrolo[3,4- d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl) benzo[d]oxazol-5-yl) methyl)-3-methyl-pyrrolidine-3- carboxylic acid

703.4 228 (R)-1-((7-cyano-2-(3′- (5-(2-(cis- 3-hydroxycyclobutyl-amino)acetyl)- 5,6-dihydro-4H-pyrrolo [3,4-dithiazol-2-yl)-2,2′-dimethylbiphenyl-3- yl)benzo[d]oxazol-5- yl)methyl)-3-methyl-

717.4 pyrrolidine-3- carboxylic acid 229 (R)-1-((7-cyano-2-(3′-(5-(2-(trans-3- hydroxycyclobutyl- amino)acetyl)- 5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′- dimethylbiphenyl-3- yl)benzo[d]oxazol-5-yl)methyl)-

717.4 3-methylpyrrolidine-3- carboxylic acid 230 2-((7-cyano-2-(3′-(5-(2-((2-hydroxyethyl) (methyl)amino) acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol- 2-yl)-2,2′- dimethylbiphenyl-3-yl)benzo[d]oxazol-5- yl)methyl)-2-azaspiro [3.3]heptane-6- carboxylicacid

717.3 231 2-((7-cyano-2-(3′-(5- (2-(((R)-1- hydroxypropan-2-yl)(methyl)amino) acetyl)-5,6-dihydro- 4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′- dimethylbiphenyl-3- yl)benzo[d]oxazol-5-yl)methyl)- 2-azaspiro[3.3]heptane- 6-carboxylic acid

731.3 232 2-((7-cyano-2-(3′-(5- (2-(((S)-1- hydroxypropan-2-yl)(methyl)amino) acetyl)-5,6- dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′- dimethylbiphenyl-3- yl)benzo[d]oxazol-5-yl)methyl)- 2-azaspiro[3.3]heptane- 6-carboxylic acid

731.3 233 2-((7-cyano-2-(3′-(5- (2-((S)-3- hydroxypyrrolidin-1-yl)acetyl)- 5,6-dihydro-4H- pyrrolo[3,4- d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3- yl)benzo[d]oxazol-5- yl)methyl)-2-

729.4 azaspiro[3.3]heptane-6- carboxylic acid 234 2-((7-cyano-2-(3′-(5-(2-((R)-3- hydroxypyrrolidin- 1-yl)acetyl)-5,6- dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′- dimethylbiphenyl-3- yl)benzo[d]oxazol-5-yl)methyl)-2-azaspiro [3.3]heptane-6-

729.4 carboxylic acid

TABLE 13 The compounds in Table 13 were prepared in accordance with thesynthetic protocols set forth in Example 105, using the appropriatestarting materials. Ex. LCMS No Name Structure [M + H] 2352-((7-cyano-2-(3′-(5-(2- (dimethylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4- d]thiazol-2-yl)-2,2′- dimethylbiphenyl-3-yl)benzo[d]oxazol-5- yl)methyl)-2- azabicyclo[2.1.1]hexane-4- carboxylicacid

673.3 236 1-((7-cyano-2-(3′-(5-(2- (dimethylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4- d]thiazol-2-yl)-2,2′- dimethylbiphenyl-3-yl)benzo[d]oxazol-5- yl)methyl)piperidine-4- carboxylic acid

675.4 237 2-((7-cyano-2-(3′-(5-(2- (dimethylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4- d]thiazol-2-yl)-2,2′- dimethylbiphenyl-3-yl)benzo[d]oxazol-5- yl)methyl)-2- azabicyclo[2.2.1]heptane-5-carboxylic acid

687.2

Example 238(R)-1-((7-cyano-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-N-(methylsulfonyl)pyrrolidine-3-carboxamide

In a dram vial,(R)-1-((7-cyano-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid (Example 63, final product: 3 mg, 0.0048 mmol) andmethanesulfonamide (2.2 mg, 0.024 mmol) were dissolved in DMF (0.3 mL).DMAP (2.9 mg, 0.024 mmol) and N,N′-dicyclohexylcarbodiimide (4.9 mg,0.024 mmol) were added to the reaction mixture in one portion. After 16h, the reaction mixture was diluted with MeOH then purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₃₈H₄₁N₆O₄S₂(M+H)⁺: m/z=709.3; found 709.2.

Example 2391-((2-(2′-chloro-3′-(6-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicAcid

Step 1:1-((2-(2′-chloro-2-methyl-3′-(4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicAcid

This compound was prepared using similar method in Example 54, Step 1-6with tert-butyl1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate (Astatech,cat #79248) replacing tert-butyl1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate in Step 1,and with azetidine-3-carboxylic acid replacing(R)-pyrrolidine-3-carboxylic acid in Step 5. The reaction mixture wasconcentrated and used in next step without further purification. LC-MScalculated for C₃₂H₂₈ClN₆O₃ (M+H)⁺: m/z=579.2; found 579.2.

Step 2:1-((2-(2′-chloro-3′-(6-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicAcid

A mixture of1-((2-(2′-chloro-2-methyl-3′-(4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicacid (10 mg, 0.017 mmol) and acetone (2.4 μL, 0.034 mmol) in DCM (169μl) was allowed to stir for 2 h. Then sodium triacetoxyborohydride (7.0mg, 0.034 mmol) was added to the mixture. After 2 h, the mixture wasconcentrated and diluted with MeOH and then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₃₅H₃₄ClN₆O₃ (M+H)⁺: m/z=621.2; found 621.2.

Example 240(R)-4-((2-(2-chloro-3′-(7-cyano-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)phenylboronicAcid

Step 1:(R)—N-(2-chloro-3′-(7-cyano-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide

This compound was prepared using similar method in Example 92, Step 1-5with (R)-pyrrolidin-3-ol replacing (S)-pyrrolidine-3-carboxylic acid inStep 5. The reaction mixture was concentrated and used in next stepwithout further purification. LC-MS calculated for C₃₄H₃₃ClN₇O₃ (M+H)⁺:m/z=622.2; found 622.3.

Step 2:(R)-4-((2-(2-chloro-3′-(7-cyano-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)phenylboronicAcid

A mixture of(R)—N-(2-chloro-3′-(7-cyano-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide(10 mg, 0.017 mmol) and 4-formylphenylboronic acid (5.1 mg, 0.034 mmol)in DCM (169 μl) was allowed to stir for 2 h. Then sodiumtriacetoxyborohydride (7.0 mg, 0.034 mmol) was added to the mixture.After 2 h, the mixture was concentrated and diluted with MeOH and thenpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as its TFA salt. LC-MS calculated for C₄₁H₄₀BClN₇O₅ (M+H)⁺:m/z=756.3; found 756.3.

Example 241(R)-1-((7-cyano-2-(3′-(5-(N-ethyl-N-methylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1:1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(ethyl(methyl)amino)ethan-1-one

This compound was prepared using similar procedures as described forExample 126, Step 2 with N-methylethanamine replacing(R)-pyrrolidin-3-ol. LC-MS calculated for C₁₇H₂₁BrN₃O₂ (M+H)⁺:m/z=378.1, 380.1; found 378.1, 380.1.

Step 2:(R)-1-((7-cyano-2-(3′-(5-(N-ethyl-N-methylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 126, Step 6 with1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(ethyl(methyl)amino)ethan-1-onereplacing(R)-1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(3-hydroxypyrrolidin-1-yl)ethan-1-one.The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₃₈H₃₉N₆O₅ (M+H)⁺: m/z=659.3; found 659.3. ¹H NMR (600MHz, DMSO) δ 8.38 (s, 1H), 8.21 (dd, J=7.9, 1.2 Hz, 1H), 8.13 (d, J=1.2Hz, 1H), 8.02-7.95 (m, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.50 (t, J=7.7 Hz,1H), 7.48-7.46 (m, 1H), 7.36 (d, J=7.6 Hz, 1H), 4.85 (s, 1H), 4.77-4.62(m, 3H), 4.61-4.48 (m, 3H), 4.38-4.16 (m, 2H), 3.90-3.08 (m, 6H), 2.83(s, 3H), 2.42 (s, 3H), 2.33 (d, J=3.3 Hz, 3H), 2.26-2.01 (m, 2H), 1.26(t, J=7.3 Hz, 3H).

Example 2422-((7-cyano-2-(3′-(5-(N-ethyl-N-methylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-2-azabicyclo[2.1.1]hexane-4-carboxylicAcid

Step 1:2-(3′-(5-(N-ethyl-N-methylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrile

This compound was prepared using similar procedures as described forExample 122, Step 8 with1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(ethyl(methyl)amino)ethan-1-one(Example 241, Step 1) replacing1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(dimethylamino)ethan-1-one.LC-MS calculated for C₃₃H₃₂N₅O₄ (M+H)⁺: m/z=562.2; found 562.2.

Step 2:2-(3′-(5-(N-ethyl-N-methylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile

This compound was prepared using similar procedures as described forExample 122, Step 9 with2-(3′-(5-(N-ethyl-N-methylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrilereplacing2-(3′-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrile.LC-MS calculated for C₃₃H₃₀N₅O₄ (M+H)⁺: m/z=560.2; found 560.2.

Step 3:2-((7-cyano-2-(3′-(5-(N-ethyl-N-methylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-2-azabicyclo[2.1.1]hexane-4-carboxylicAcid

To a mixture of2-(3′-(5-(N-ethyl-N-methylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile(10.0 mg, 0.018 mmol),2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid (4.1mg, 0.018 mmol) in DCM (0.5 ml) was added DIEA (3.2 μl, 0.018 mmol).After stirring at room temperature for 2.5 h, sodiumtriacetoxyborohydride (7.6 mg, 0.036 mmol) was added and the reactionmixture was stirred overnight. After removal of solvent, the residue wasdissolved in methanol and water and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₃₉H₃₉N₆O₅ (M+H)⁺: m/z=671.3; found 671.3.

TABLE 14 The compounds in Table 14 were prepared in accordance with thesynthetic protocols set forth in Example 242, using the appropriatestarting materials. Ex. LCMS No. Name/¹HNMR Structure [M + H] 243(R)-1-((7-cyano-2-(3′-(5- (N-ethyl-N-methylglycyl)-5,6-dihydro-4H-pyrrolo[3,4- d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3- yl)benzo[d]oxazol-5- yl)methyl)-3-methylpyrrolidine-3- carboxylic acid ¹H NMR (500 MHz, DMSO) δ 8.39 (s,1H), 8.21 (d, J = 6.9 Hz, 1H),

673.3 8.13 (s, 1H), 7.98 (t, J = 7.2 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H),7.50 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 6.9 Hz, 1H), 7.36 (d, J = 7.6 Hz,1H), 4.85 (s, 1H), 4.72 (s, 1H), 4.66 (s, 1H), 4.58 (s, 2H), 4.54 (s,1H), 4.38-4.15 (m, 2H), 3.87-3.36 (m, 4H), 3.30-3.07 (m, 2H), 2.83 (s,3H), 2.49-2.31 (m, 1H), 2.42 (s, 3H), 2.33 (s, 3H), 2.12- 1.76 (m, 1H),1.44-1.30 (m, 3H), 1.26 (t, J = 7.3 Hz, 3H). 2441-((7-cyano-2-(3′-(5-(N- ethyl-N-methylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d] oxazol-2-yl)-2,2′- dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5- yl)methyl)piperidine-4- carboxylic acid

673.3 245 (R)-1-((7-cyano-2-(3′-(5- (dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4- d]oxazol-2-yl)-2,2′- dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl) methyl)-3- methylpyrrolidine- 3-carboxylic acid

659.3 246 1-((7-cyano-2-(3′-(5- (dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d] oxazol-2-yl)-2,2′- dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5- yl)methyl)piperidine-4- carboxylic acid

659.3 247 (R)-1-((7-cyano-2-(3′-(5- (2-((R)-3-hydroxy-pyrrolidin-1-yl)acetyl)- 5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′- dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl) methyl)-3-methyl- pyrrolidine-3-carboxylic acid

701.3 248 (R)-1-((7-cyano-2-(3′-(5- (N-isopropyl-N- methylglycyl)-5,6-dihydro-4H-pyrrolo[3,4- d]oxazol-2-yl)-2,2′- dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5- yl)methyl)-3-methyl- pyrrolidine-3-carboxylicacid

687.3 249 (R)-1-((7-cyano-2-(3′-(5-(2- (4-hydroxypiperidin-1-yl)acetyl)-5,6-dihydro-4H- pyrrolo[3,4-d]oxazol-2- yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d] oxazol-5-yl)methyl)-3- methylpyrrolidine-3-carboxylic acid

715.3 250 (R)-1-((7-cyano-2-(3′-(5- (2-(4-hydroxypiperidin-1-yl)acetyl)-5,6-dihydro- 4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′- biphenyl]-3-yl)benzo[d] oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid

701.3 251 2-((7-cyano-2-(3′-(5-(2-(4- hydroxypiperidin-1-yl)acetyl)-5,6-dihydro-4H- pyrrolo[3,4-d]oxazol-2- yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d] oxazol-5-yl)methyl)-2- azabicyclo[2.2.1]heptane-5-carboxylic acid

727.3 252 (R)-1-((7-cyano-2-(3′-(5- (N-(2-hydroxyethyl)-N-methylglycyl)-5,6- dihydro-4H-pyrrolo[3,4- d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]- 3-yl)benzo[d]oxazol-5- yl)methyl)-3-methyl-pyrrolidine-3-carboxylic acid

689.3 253 2-((7-cyano-2-(2,2′- dimethyl-3′-(5-(2-(4-methylpiperazin-1-yl) acetyl)-5,6-dihydro- 4H-pyrrolo[3,4-d]oxazol-2-yl)-[1,1′-biphenyl]-3- yl)benzo[d]oxazol-5-yl) methyl)-2-azabicyclo[2.2.1]heptane-5-

726.3 carboxylic acid 254 (R)-1-((7-cyano-2-(2,2′- dimethyl-3′-(5-(2-(4-methylpiperazin-1- yl)acetyl)-5,6-dihydro- 4H-pyrrolo[3,4-d]oxazol-2-yl)-[1,1′- biphenyl]-3-yl)benzo [d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3- carboxylic acid

714.3 255 (3R)-1-((7-cyano-2- (2,2′-dimethyl-3′-(5- (2-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl) biphenyl-3-yl)benzo[d] oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid

712.3

Example 256(R)-1-((2-(2′-chloro-3′-(5-(2-((R)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

Step 1: 2-(3-bromo-2-chlorophenyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazole

This compound was prepared using similar procedures as described forExample 122, Step 1-6, with 3-bromo-2-chlorobenzoic acid replacing3-bromo-2-methylbenzoic acid in Step 3. LC-MS calculated forC₁₁H₉BrClN₂O (M+H)⁺: m/z=299.0, 301.0; found 299.0, 301.0.

Step 2:1-(2-(3-bromo-2-chlorophenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-chloroethan-1-one

This compound was prepared using similar procedures as described forExample 126, Step 1 with2-(3-bromo-2-chlorophenyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazolereplacing2-(3-bromo-2-methylphenyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazole. LC-MScalculated for C₁₃H₁₀BrCl₂N₂O₂ (M+H)⁺: m/z=374.9, 376.9; found 374.9,376.9.

Step 3:(R)-1-(2-(3-bromo-2-chlorophenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(3-hydroxypyrrolidin-1-yl)ethan-1-one

The mixture of1-(2-(3-bromo-2-chlorophenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-chloroethan-1-one(154 mg, 0.410 mmol), (R)-pyrrolidin-3-ol (35.7 mg, 0.410 mmol), TEA(0.171 ml, 1.229 mmol) and DMF (1.0 ml) was heated at 60° C. for 2 h.The reaction mixture was diluted with methanol and 1 N HCl and purifiedwith prep-LCMS (pH=2, acetonitrile/water+TFA) to give the desiredproduct (165 mg, 94%). LC-MS calculated for C₁₇H₁₈BrClN₃O₃ (M+H)⁺:m/z=426.0, 428.0; found 426.0, 428.0.

Step 4:(R)-1-((2-(2′-chloro-3′-(5-(2-((R)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicAcid

This compound was prepared using similar procedures as described forExample 126, Step 6 with(R)-1-(2-(3-bromo-2-chlorophenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(3-hydroxypyrrolidin-1-yl)ethan-1-onereplacing(R)-1-(2-(3-bromo-2-methylphenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-(3-hydroxypyrrolidin-1-yl)ethan-1-one.The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₃₈H₃₆ClN₆O₆ (M+H)⁺: m/z=707.2; found 707.2.

TABLE 15 The compounds in Table 15 were prepared in accordance with thesynthetic protocols set forth in Example 146, using the appropriateamino alcohols. Ex. LCMS No. Name Structure [M + H] 257(R)-1-((7-cyano-2-(3′-(3- (((S)-1-hydroxypropan-2- ylamino)methyl)-1,7-naphthyridin-8-ylamino)- 2,2′-dimethylbiphenyl-3- yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-

682.2 carboxylic acid 258 (R)-1-((7-cyano-2-(3′-(3-(((R)-1-hydroxypropan-2- ylamino)methyl)- 1,7-naphthyridin-8-ylamino)-2,2′- dimethylbiphenyl-3- yl)benzo[d]oxazol-5-

682.2 yl)methyl)pyrrolidine-3- carboxylic acid

TABLE 16 The compounds in Table 16 were prepared in accordance with thesynthetic protocols set forth in Example 36, using the appropriatestarting materials. Ex. LCMS No. Name Structure [M + H] 2591-((7-cyano-2-(3′-(1,5- dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2- carboxamido)-2,2′- dimethylbiphenyl-3-yl)benzo[d]oxazol-5- yl)methyl)piperidine-4- carboxylic acid

658.3 260 (R)-1-(7-cyano-2-(3′-(1,5- dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2- carboxamido)-2,2′- dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl) methyl)-3-methylpyrrolidine- 3-carboxylic acid

658.3

Example 261trans-4-((2-(2-chloro-3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylicAcid

Step 1:(R)—N-(2-chloro-3′-(7-cyano-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide

This compound was prepared using similar procedures as described forExample 92 with (R)-pyrrolidin-3-ol replacing(S)-pyrrolidine-3-carboxylic acid in Step 4. LC-MS calculated forC₃₄H₃₃ClN₇O₃ (M+H)⁺: m/z=622.1; found 622.2.

Step 2:trans-4-((2-(2-chloro-3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylicAcid

To a solution of(R)—N-(2-chloro-3′-(7-cyano-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide(40 mg, 0.064 mmol) in DCM (5 ml) was added methyltrans-4-formylcyclohexane-1-carboxylate (22 mg, 0.13 mmol) and DIEA(0.034 mL, 0.193 mmol). The mixture was stirred at r.t. for 60 min. Thensodium triacetoxyborohydride (41 mg, 0.19 mmol) was added. The reactionmixture was continued to stir at r.t. overnight. The reaction mixturewas diluted with DCM, washed by NaHCO₃ aqueous solution, water, andbrine. The organic phase was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. To a solution of above residue inTHF (2 mL) was added lithium hydroxide (6.2 mg, 0.26 mmol) and a fewdrops of water. The reaction mixture was stirred at 40° C. for two days.The reaction mixture was diluted with MeCN/water, and purified viaprep-HPLC (pH=2, MeCN/water with TFA) to give the desired product as theTFA salt. LC-MS calculated for C₄₂H₄₅ClN₇O₅ (M+H)⁺: m/z=762.3; found762.2. ¹H NMR (500 MHz, DMSO) δ 9.94 (s, 1H), 8.40 (s, 1H), 8.30 (d,J=8.3 Hz, 1H), 8.21 (d, J=7.9 Hz, 1H), 8.14 (s, 1H), 7.59 (t, J=7.8 Hz,1H), 7.52 (t, J=7.9 Hz, 1H), 7.48 (d, J=6.8 Hz, 1H), 7.20 (dd, J=7.6,1.4 Hz, 1H), 4.67-4.15 (m, 5H), 3.95 (s, 3H), 3.87-2.95 (m, 10H), 2.46(s, 3H), 2.33-2.22 (m, 1H), 2.15 (t, J=12.2 Hz, 1H), 2.03-1.94 (m, 1H),1.94-1.74 (m, 5H), 1.47-1.24 (m, 2H), 1.09-0.90 (m, 2H).

TABLE 17 The compounds in Table 17 were prepared in accordance with thesynthetic protocols set forth in Example 261, using the appropriatestarting materials. Ex. LCMS No. Name Structure [M + H] 262(R)-3-((2-(2-chloro-3′-(7- cyano-5-((3- hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2- yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7- dihydro-1H-imidazo[4,5- c]pyridin-5(4H)-yl)methyl)bicyclo[1.1.1]

746.2 pentane-1-carboxylic acid 263 (R)-3-(2-(2-chloro-3′-(7-cyano-5-((3- hydroxypyrrolidin-1- yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3- ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5- c]pyridin-5(4H)-yl)-1-methylcyclobutanecarboxylic acid

734.2 264 4-(2-(2-chloro-3′-(7-cyano-5- (((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2- yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7- dihydro-1H-imidazo[4,5- c]pyridin-5(4H)-yl)cycloheptane carboxylic acid

762.3 265 (R)-4-(2-(2-(2-chloro-3′-(7- cyano-5-((3- hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2- yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7- dihydro-1H-imidazo[4,5- c]pyridin-5(4H)-yl)ethyl)cyclohexane carboxylic acid

776.2 266 cis-4-((2-(2-chloro-3′-(7- cyano-5-(((R)-3-hydroxypyrrolidin-1- yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3- ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5- c]pyridin-5(4H)-

762.3 yl)methyl)cyclohexane carboxylic acid

Example 267(R)-4-((2-(2-chloro-3′-(7-cyano-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)bicyclo[2.2.1]heptane-1-carboxylicAcid

Step 1: methyl 4-formylbicyclo[2.2.1]heptane-1-carboxylate

A mixture of methyl 4-(hydroxymethyl)bicyclo[2.2.1]heptane-1-carboxylate(400 mg, 2.171 mmol) and Dess-Martin periodinane (1381 mg, 3.26 mmol) inDCM (12.0 mL) was stirred at room temperature for 3 h. The reactionmixture was quenched with 20% aqueous Na₂S₂O₃ solution and saturatedNaHCO₃ solution, and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude product was used directlyin the next step without further purification.

Step 2:(R)-4-((2-(2-chloro-3′-(7-cyano-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)bicyclo[2.2.1]heptane-1-carboxylicAcid

To a solution of(R)—N-(2-chloro-3′-(7-cyano-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide(Example 261, Step 1: 10 mg, 0.016 mmol) in DCM (5 ml) was added methyl4-formylbicyclo[2.2.1]heptane-1-carboxylate (8.8 mg, 0.048 mmol) andDIEA (0.008 ml, 0.048 mmol). The mixture was stirred at r.t. for 60 min.Then sodium triace-toxyborohydride (10.2 mg, 0.048 mmol) was added. Thereaction mixture was continued to stir at r.t. overnight. The reactionmixture was diluted with DCM, washed by NaHCO₃ aqueous solution, water,and brine. The organic phase was dried over MgSO₄, filtered andconcentrated under reduced pressure. To a solution of above residue inTHF (2 mL) was added lithium hydroxide (3.8 mg, 0.16 mmol) and a fewdrops of water. The reaction mixture was stirred at 40° C. for two days.The reaction mixture was diluted with MeCN/water, and purified viaprep-HPLC (pH=2, MeCN/water with TFA) to give the desired product as theTFA salt. LC-MS calculated for C₄₃H₄₅ClN₇O₅ (M+H)⁺: m/z=774.3; found774.3. ¹H NMR (600 MHz, DMSO) δ 9.95 (s, 1H), 8.40 (d, J=12.6 Hz, 1H),8.28 (d, J=7.0 Hz, 1H), 8.21 (d, J=7.8 Hz, 1H), 8.14 (d, J=8.9 Hz, 1H),7.60 (t, J=7.6 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H),7.20 (d, J=7.2 Hz, 1H), 4.69-4.20 (m, 5H), 3.96 (s, 3H), 3.82-3.16 (m,8H), 3.07 (s, 2H), 2.46 (s, 3H), 2.28 (d, J=6.4 Hz, 1H), 2.05-1.49 (m,11H).

Example 268(R)-4-((2-(2-chloro-3′-(7-cyano-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)-1-methylcyclohexanecarboxylicAcid (Peak 1)

Step 1: 4-formyl-1-methylcyclohexanecarboxylic Acid

To a solution of methyl 4-formyl-1-methylcyclohexane-1-carboxylate (J&WPharmLab, cat #10R0682: 14.8 mg, 0.080 mmol) in THF/MeOH (2/1 v/v, 3 mL)was added lithium hydroxide (3.8 mg, 0.16 mmol) and water (1 mL). Thereaction mixture was stirred at 40° C. overnight. Then the mixture wasconcentrated and the residue was dissolved in DCM. After acidificationwith 1N HCl aqueous solution to pH=4, the mixture was extracted with DCMand the combined organic layers were washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The crudeproduct was used directly in the next step without further purification.

Step 2:(R)-4-((2-(2-chloro-3′-(7-cyano-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)-1-methylcyclohexanecarboxylicAcid

To a solution of(R)—N-(2-chloro-3′-(7-cyano-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide(Example 261, Step 1: 10 mg, 0.016 mmol) in DCM (1 ml) was added4-formyl-1-methylcyclohexanecarboxylic acid (13.6 mg, 0.080 mmol) andDIEA (0.008 ml, 0.048 mmol). The mixture was stirred at r.t. for 60 min.Then sodium triacetoxy-borohydride (10.2 mg, 0.048 mmol) was added. Thereaction mixture was continued to stir at r.t. for 2 hrs. The reactionmixture was concentrated, then diluted with MeCN/water, and purified viaprep-HPLC (pH=2, MeCN/water with TFA) to give two desired products(cis/trans isomers) as the TFA salt.

Peak 1: retention time on analytical LC-MS (pH=2,acetonitrile/water+TFA) t_(r)=1.98 min, LC-MS calculated forC₄₃H₄₇ClN₇O₅ (M+H)⁺: m/z=776.3; found 776.3.

Example 269(R)-4-((2-(2-chloro-3′-(7-cyano-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)-1-methylcyclohexanecarboxylicAcid (Peak 2)

This compound was prepared using the same procedures as described forExample 268. In the prep-HPLC (pH=2, acetonitrile/water+TFA), the seconddesired peak was collected to give the desired product as TFA salt. Peak2: retention time on analytical LC-MS (pH=2, acetonitrile/water+TFA)t_(r)=2.00 min, LC-MS calculated for C₄₃H₄₇ClN₇O₅ (M+H)⁺: m/z=776.3;found 776.3.

Example 270trans-4-((2-(2-chloro-3′-(7-cyano-5-((5-hydroxy-2-azabicyclo[2.2.1]heptan-2-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylicAcid

Step 1: trans-methyl4-((2-(2-chloro-3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylate

To a solution of tert-butyl2-(2-chloro-3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(Example 92, Step 2: 200.0 mg, 0.306 mmol) in DCM (5 mL) was added HCl(4M in dioxane, 0.383 ml). The solution was stirred at r.t. for 2 hours,then concentrated to dryness. To a solution of the above residue in DCM(5 ml) was added methyl trans-4-formylcyclohexane-1-carboxylate (104 mg,0.612 mmol) and DIEA (0.160 ml, 0.919 mmol). The mixture was stir atr.t. for 60 min. Then sodium triacetoxyborohydride (195 mg, 0.919 mmol)was added, the reaction mixture was stirred at r.t. overnight. Thereaction solution was diluted with DCM, then washed with aqueous NaHCO₃solution, water and brine. The organic layer was dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography eluting with 5% MeOH in DCM togive desired product. LC-MS calculated for C₃₉H₄₀ClN₆O₅ (M+H)⁺:m/z=707.3; found: 707.3.

Step 2: trans-methyl4-((2-(2-chloro-3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylate

To a stirred solution of trans-methyl4-((2-(2-chloro-3′-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylate(175 mg, 0.247 mmol) in DCM (5.0 ml) was added sodium bicarbonate (208mg, 2.474 mmol) and dess-martin periodinane (126 mg, 0.297 mmol). Theresulted mixture was stirred at r.t. for 1 hour. The reaction solutionwas diluted with DCM, then washed with aqueous NaHCO₃ solution, water,and brine. The organic layer was dried over Na₂SO₄, filtered, andconcentrated under reduce pressure. The residue was purified by silicagel chromatography eluting with 5% MeOH in DCM to give the desiredproduct. LC-MS calculated for C₃₉H₃₈ClN₆O₅ (M+H)⁺: m/z=705.2; found:705.2.

Step 3:trans-4-((2-(2-chloro-3′-(7-cyano-5-((5-hydroxy-2-azabicyclo[2.2.1]heptan-2-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylicAcid

To a solution of trans-methyl4-((2-(2-chloro-3′-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylate(20 mg, 0.028 mmol) in DCM (2 mL) was added2-azabicyclo[2.2.1]heptan-5-ol HCl salt (8.5 mg, 0.057 mmol) and DIEA(0.015 mL, 0.085 mmol). The mixture was stirred at r.t. for 30 min. Thensodium triacetoxyborohydride (18.0 mg, 0.085 mmol) was added. Thereaction mixture was continued to stir at r.t. overnight. The reactionmixture was diluted with DCM, washed by NaHCO₃ aqueous solution, waterand brine. The organic layer was dried over MgSO₄, filtered andconcentrated under reduced pressure. To a solution of the above residuein THF (2 mL) was added lithium hydroxide (6.2 mg, 0.26 mmol) and a fewdrops of water. The reaction mixture was stirred at 40° C. for two days.The reaction mixture was diluted with MeCN/Water, and purified viaprep-HPLC (pH=2, MeCN/water with TFA) to give the desired product as theTFA salt. LC-MS calculated for C₄₄H₄₇ClN₇O₅ (M+H)⁺: m/z=788.3; found788.3.

Example 271trans-4-((2-(2-chloro-3′-(7-cyano-5-(pyrrolidin-1-ylmethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylicAcid

This compound was prepared using similar procedures as described forExample 270 with pyrrolidine replacing 2-azabicyclo[2.2.1]heptan-5-ol inStep 3. The reaction mixture was concentrated, then diluted inMeCN/Water, filtered then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₄₂H₄₅ClN₇O₄ (M+H)⁺: m/z=746.3; found 746.3.

Example A. PD-1/PD-L1 Homogeneous Time-Resolved Fluorescence (HTRF)Binding Assay

The assays were conducted in a standard black 384-well polystyrene platewith a final volume of 20 μL. Inhibitors were first serially diluted inDMSO and then added to the plate wells before the addition of otherreaction components. The final concentration of DMSO in the assay was1%. The assays were carried out at 25° C. in the PBS buffer (pH 7.4)with 0.05% Tween-20 and 0.1% BSA. Recombinant human PD-L1 protein(19-238) with a His-tag at the C-terminus was purchased fromAcroBiosystems (PD1-H5229). Recombinant human PD-1 protein (25-167) withFc tag at the C-terminus was also purchased from AcroBiosystems(PD1-H5257). PD-L1 and PD-1 proteins were diluted in the assay bufferand 10 μL was added to the plate well. Plates were centrifuged andproteins were preincubated with inhibitors for 40 minutes. Theincubation was followed by the addition of 10 μL of HTRF detectionbuffer supplemented with Europium cryptate-labeled anti-human IgG(PerkinElmer-AD0212) specific for Fc and anti-His antibody conjugated toSureLight®-Allophycocyanin (APC, PerkinElmer-AD0059H). Aftercentrifugation, the plate was incubated at 25° C. for 60 min. beforereading on a PHERAstar FS plate reader (665 nm/620 nm ratio). Finalconcentrations in the assay were—3 nM PD1, 10 nM PD-L1, 1 nM europiumanti-human IgG and 20 nM anti-His-Allophycocyanin. IC₅₀ determinationwas performed by fitting the curve of percent control activity versusthe log of the inhibitor concentration using the GraphPad Prism 5.0software.

Compounds of the present disclosure, as exemplified in Examples 1-9,showed IC₅₀ values in the following ranges: +=IC₅₀≤10 nM; ++=10nM<IC₅₀≤100 nM; +++=100 nM<IC₅₀≤1000 nM

Data obtained for the Example compounds using the PD-1/PD-L1 homogenoustime-resolved fluorescence (HTRF) binding assay described in Example Ais provided in Table 1A.

TABLE 1A PD-1/PD-L1 HTRF Example IC₅₀ (nM) 1 + 2 + 3 + 4 + 5 + 6 + 7 +8 + 9 + 10 + 11 + 12 + 13 + 14 + 15 + 16 + 17 + 18 + 19 + 20 + 21 + 22 +23 + 24 + 25 + 26 + 27 + 28 + 29 + 30 + 31 + 32 + 33 + 34 + 35 + 36 +37 + 38 + 39 + 40 ++ 41 + 42 + 43 + 44 + 45 + 46 + 47 + 48 + 49 + 50 +51 + 52 + 53 + 54 + 55 + 56 + 57 + 58 + 59 + 60 + 61 + 62 + 63 + 64 +65 + 66 + 67 + 68 + 69 + 70 + 71 + 72 + 73 + 74 + 75 + 76 + 77 + 78 +79 + 80 + 81 + 82 + 83 + 84 + 85 + 86 + 87 + 88 + 89 + 90 + 91 + 92 +93 + 94 + 95 + 96 + 97 + 98 + 99 + 100 + 101 + 102 + 103 + 104 + 105 +106 + 107 + 108 + 109 + 110 + 111 + 112 + 113 + 114 + 115 + 116 + 117 +118 + 119 + 120 + 121 + 122 + 123 + 124 + 125 + 126 + 127 + 128 + 129 +130 + 131 + 132 + 133 + 134 + 135 + 136 + 137 + 138 + 139 + 140 + 141 +142 + 143 + 144 + 145 + 146 + 147 + 148 + 149 ++ 150 ++ 151 + 152 +153 + 154 + 155 + 156 + 157 + 158 + 159 + 160 + 161 + 162 + 163 + 164 +165 + 166 + 167 + 168 + 169 + 170 + 171 + 172 + 173 + 174 + 175 + 176 +177 + 178 + 179 + 180 + 181 + 182 + 183 + 184 + 185 + 186 + 187 + 188 +189 + 190 + 191 + 192 + 193 + 194 + 195 + 196 + 197 + 198 + 199 + 200 +201 + 202 + 203 + 204 + 205 + 206 + 207 + 208 + 209 + 210 + 211 + 212 +213 + 214 + 215 + 216 + 217 + 218 + 219 + 220 + 221 + 222 + 223 + 224 +225 + 226 + 227 + 228 + 229 + 230 + 231 + 232 + 233 + 234 + 235 + 236 +237 + 238 + 239 + 240 + 241 + 242 + 243 + 244 + 245 + 246 + 247 + 248 +249 + 250 + 251 + 252 + 253 + 254 + 255 + 256 + 257 + 258 + 259 + 260 +261 + 262 + 263 + 264 + 265 + 266 + 267 + 268 + 269 + 270 + 271 +

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including withoutlimitation all patent, patent applications, and publications, cited inthe present application is incorporated herein by reference in itsentirety.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein: ring A is 5- to 14-membered heteroaryl, 4- to 14-memberedheterocycloalkyl, C₆₋₁₀ aryl or C₃₋₁₄ cycloalkyl, wherein the 5- to14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each has1-4 heteroatoms as ring members selected from B, P, N, O and S, whereinthe P, N or S atom as ring members is optionally oxidized and one ormore carbon atoms as ring members are each optionally replaced by acarbonyl group; and wherein ring A is optionally substituted with 1, 2,3, 4 or 5 R⁶ substituents; L is a bond, —C(O)NR¹³—, —NR¹³C(O)—,—C(═S)NR¹³—, —NR¹³C(═S)—, —C(═NR¹³)NR¹³—, —NR¹³C(═NR¹³)—,—C(═NOR¹³)NR¹³—, —NR¹³C(═NOR¹³)—, —C(═NCN)NR¹³—, —NR¹³C(═NCN)—, O,—(CR¹⁴R¹⁵)_(q)—, —(CR¹⁴R¹⁵)_(q)—O—, —O(CR¹⁴R¹⁵)_(q)—, —NR¹³—,—(CR¹⁴R¹⁵)_(q)—NR¹³—, —NR¹³—(CR¹⁴R¹⁵)_(q)—, —CH═CH—, —C≡C—, —SO₂NR¹³—,—NR¹³SO₂—, —NR¹³SO₂NR¹³—, —NR¹³C(O)O—, —OC(O)NR¹³— or —NR¹³C(O)NR¹³—; R³is methyl, halo, CN or C₁₋₄ haloalkyl; R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkylor —N(C₁₋₄ alkyl)₂; R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;R⁶ and R¹⁷ are each independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), C(O)NR^(a)S(O)₂R^(a),OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a),NR^(a)C(═NR^(a))R^(a), NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a),C(═NR^(a))R^(a), C(═NOH)R^(a), C(═NOH)NR^(a), C(═NCN)NR^(a)R^(a),NR^(a)C(═NCN)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a),S(O)₂NR^(a)C(O)R^(a), —P(O)R^(a)R^(a), —P(O)(OR^(a))(OR^(a)), —B(OH)₂,—B(OR^(a))₂ and S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl,4-14 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14membered heterocycloalkyl)-C₁₋₄ alkyl- of R⁶ and R¹⁷ are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents; or two R⁶ substituents attached to the same ring carbonatom taken together with the ring carbon atom to which they are attachedform spiro C₃₋₆ cycloalkyl or spiro 4- to 7-membered heterocycloalkyl,each of which is optionally substituted with 1, 2, or 3 independentlyselected R^(f) substituents; each R¹³ is independently H, C₁₋₆ haloalkylor C₁₋₆ alkyl optionally substituted with a substituent selected fromC₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH,—COOH, NH₂, —NHC₁₋₄ alkyl and —N(C₁₋₄ alkyl)₂; R¹⁴ and R¹⁵ are eachindependently selected from H, halo, CN, OH, —COOH, C₁₋₄ alkyl, C₁₋₄alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and4-6 membered heterocycloalkyl of R¹⁴ or R¹⁵ are each optionallysubstituted with 1, 2, or 3 independently selected R^(q) substituents;or R¹⁴ and R¹⁵ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5-, 6- or7-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 independently selected R^(q) substituents; each R^(a) isindependently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14 memberedheteroaryl, 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-,and (4-14 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14membered heteroaryl, 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl- and (4-14 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(a) areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(d) substituents; each R^(d) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₄cycloalkyl, 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-,(4-14 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e),SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), C(O)NR^(e)S(O)₂R^(e),OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(═NR^(e))R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), S(O)₂NR^(e)C(O)R^(e), NR^(e)S(O)₂R^(e),NR^(e)S(O)₂NR^(e)R^(e), —P(O)R^(e)R^(e), —P(O)(OR^(e))(OR^(e)), —B(OH)₂,—B(OR^(e))₂ and S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, 5-14 membered heteroaryl, C₃₋₁₄ cycloalkyl, 4-14membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are each optionally substitutedwith 1, 2, or 3 independently selected R^(f) substituents; each R^(e) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(e) are each optionally substituted with 1, 2 or 3 independentlyselected R^(f) substituents; each R^(b) substituent is independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂,NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),C(O)NR^(c)S(O)₂R^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NOH)R^(c),C(═NOH)NR^(c), C(═NCN)NR^(c)R^(c), NR^(c)C(═NCN)NR^(c)R^(c),C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c),NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(═NR^(c))R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c),S(O)₂NR^(c)C(O)R^(c), —P(O)R^(c)R^(c), —P(O)(OR^(c))(OR^(c)), —B(OH)₂,—B(OR^(c))₂ and S(O)₂NR^(c)R^(c); wherein the C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each further optionallysubstituted with 1, 2 or 3 independently selected R^(d) substituents;each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(f) substituents; each R^(f) is independently selected from C₁₋₄alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,halo, CN, NHOR^(g), OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g),C(O)OR^(g), C(O)NR^(g)S(O)₂R^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g),NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(═NR^(g))R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),S(O)₂NR^(g)C(O)R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g),—P(O)R^(g)R^(g), —P(O)(OR^(g))(OR^(g)), —B(OH)₂, —B(OR^(g))₂ andS(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are eachoptionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(n) substituents; each R^(n) is substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(o), OR^(o), SR^(o),C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), C(O)NR^(o)S(O)₂R^(o),OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(═NR^(o))R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o),S(O)NR^(o)R^(o), S(O)₂R^(o), S(O)₂NR^(o)C(O)R^(o), NR^(o)S(O)₂R^(o),NR^(o)S(O)₂NR^(o)R^(o), —P(O)R^(o)R^(o), —P(O)(OR^(o))(OR^(o)), —B(OH)₂,—B(OR^(o))₂ and S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- of R^(n) are each optionally substituted with 1, 2 or 3independently selected R^(q) substituents; each R^(g) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) are each optionallysubstituted with 1, 2, or 3 independently selected R^(p) substituents;each R^(p) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(r),OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r),C(O)NR^(r)S(O)₂R^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r),NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(═NR^(r))R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),S(O)₂NR^(r)C(O)R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r),—P(O)R^(r)R^(r), —P(O)(OR^(r))(OR^(r)), —B(OH)₂, —B(OR^(r))₂ andS(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(p) is optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents; orany two R^(a) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2or 3 independently selected R^(h) substituents; each R^(h) isindependently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i),NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i), C(O)NR^(i)S(O)₂R^(i),OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(═NR^(i))R^(i), NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i),C(═NR^(i))NR^(i)R^(i), NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i),S(O)NR^(i)R^(i), S(O)₂R^(i), S(O)₂NR^(i)C(O)R^(i), NR^(i)S(O)₂R^(i),NR^(i) S(O)₂NR^(i)R^(i), —P(O)R^(i)R^(i), —P(O)(OR^(i))(OR^(i)),—B(OH)₂, —B(OR^(i))₂ and S(O)₂NR^(i)R^(i), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(h) are each furtheroptionally substituted by 1, 2, or 3 independently selected R^(j)substituents; each R^(j) is independently selected from C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, CN, NHOR^(k), OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k),C(O)OR^(k), C(O)NR^(k)S(O)₂R^(k), OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k),NR^(k)R^(k), NR^(k)C(O)R^(k), NR^(k)C(═NR^(k))R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),S(O)₂NR^(k)C(O)R^(k), NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k),—P(O)R^(k)R^(k), —P(O)(OR^(k))(OR^(k)), —B(OH)₂, —B(OR^(k))₂ andS(O)₂NR^(k)R^(k), wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl,5- or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy of R^(j) areeach optionally substituted with 1, 2 or 3 independently selected R^(q)substituents; or two R^(h) groups attached to the same carbon atom ofthe 4- to 10-membered heterocycloalkyl taken together with the carbonatom to which they are attached form a C₃₋₆ cycloalkyl or 4- to6-membered heterocycloalkyl having 1-2 heteroatoms as ring membersselected from O, N or S; or any two R^(c) substituents together with theboron, phosphorus or nitrogen atom to which they are attached form a 4-,5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 independently selected R^(h) substituents;or any two R^(e) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(h) substituents; or any two R^(g)substituents together with the boron, phosphorus or nitrogen atom towhich they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; or any two R^(i) substituentstogether with the boron, phosphorus or nitrogen atom to which they areattached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents, or 1, 2, or 3 independently selected R^(q)substituents; or any two R^(k) substituents together with the boron,phosphorus or nitrogen atom to which they are attached form a 4-, 5-,6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 independently selected R^(h) substituents,or 1, 2, or 3 independently selected R^(q) substituents; or any twoR^(o) substituents together with the boron, phosphorus or nitrogen atomto which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; or any two R^(r) substituentstogether with the boron, phosphorus or nitrogen atom to which they areattached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents; each R^(i), R^(k), R^(o) or R^(r) is independentlyselected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl,C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7 memberedheterocycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl of R^(i), R^(k), R^(o)or R^(r) are each optionally substituted with 1, 2 or 3 independentlyselected R^(q) substituents; each R^(q) is independently selected fromhalo, OH, CN, —COOH, NH₂, —NH—C₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, phenyl,5-6 membered heteroaryl, 4-6 membered heterocycloalkyl and C₃₋₆cycloalkyl, wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6membered heterocycloalkyl, and 5-6 membered heteroaryl of R^(q) are eachoptionally substituted with 1, 2 or 3 substituents independentlyselected from halo, OH, CN, —COOH, NH₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀ cycloalkyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl; the subscript m is aninteger of 0, 1, 2 or 3; the subscript n is an integer of 0, 1, 2 or 3;each subscript q is independently an integer of 1, 2, 3 or 4; and thesubscript s is an integer of 1, 2, 3 or
 4. 2. The compound of claim 1,having Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein: ring A is 5- to 14-membered heteroaryl, 4- to 14-memberedheterocycloalkyl, C₆₋₁₀ aryl or C₃₋₁₄ cycloalkyl, wherein the 5- to14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each has1-4 heteroatoms as ring members selected from B, P, N, O and S, whereinthe P, N or S atom as ring members is optionally oxidized and one ormore carbon atoms as ring members are each optionally replaced by acarbonyl group; and wherein ring A is optionally substituted with 1, 2,3, 4 or 5 R⁶ substituents; L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, O,—(CR¹⁴R¹⁵)_(q)—, —(CR¹⁴R¹⁵)_(q)—O—, —O(CR¹⁴R¹⁵)_(q)—, —NR¹³—,—(CR¹⁴R¹⁵)_(q)—NR¹³—, —NR¹³—(CR¹⁴R¹⁵)_(q)—, —CH═CH—, —C≡C—, —SO₂NR¹³—,—NR¹³SO₂—, —NR¹³SO₂NR¹³—, —NR¹³C(O)O—, —OC(O)NR¹³— or —NR¹³C(O)NR¹³—; R³is methyl, halo, CN or C₁₋₄ haloalkyl; R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkylor —N(C₁₋₄ alkyl)₂; R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;R⁶ and R¹⁷ are each independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NOH)R^(a), C(═NOH)NR^(a),C(═NCN)NR^(a)R^(a), NR^(a)C(═NCN)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a),—P(O)R^(a)R^(a), —P(O)(OR^(a))(OR^(a)), —B(OH)₂, —B(OR^(a))₂ andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁶ and R¹⁷ are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents; or two R⁶ substituents attached to the same ring carbonatom taken together with the ring carbon atom to which they are attachedform spiro C₃₋₆ cycloalkyl or spiro 4- to 7-membered heterocycloalkyl,each of which is optionally substituted with 1, 2, or 3 independentlyselected R^(f) substituents; each R¹³ is independently H, C₁₋₆ haloalkylor C₁₋₆ alkyl optionally substituted with a substituent selected fromC₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH,—COOH, NH₂, —NHC₁₋₄ alkyl and —N(C₁₋₄ alkyl)₂; R¹⁴ and R¹⁵ are eachindependently selected from H, halo, CN, OH, —COOH, C₁₋₄ alkyl, C₁₋₄alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and4-6 membered heterocycloalkyl of R¹⁴ or R¹⁵ are each optionallysubstituted with 1, 2, or 3 independently selected R^(q) substituents;or R¹⁴ and R¹⁵ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5-, 6- or7-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 independently selected R^(q) substituents; each R^(a) isindependently selected from H, CN, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14 memberedheteroaryl, 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-,and (4-14 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14membered heteroaryl, 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl- and (4-14 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(a) areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(d) substituents; each R^(d) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₄cycloalkyl, 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-,(4-14 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e),SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e),OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NOH)NR^(e)R^(e),NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e),NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), —P(O)R^(e)R^(e),—P(O)(OR^(e))(OR^(e)), —B(OH)₂, —B(OR^(e))₂ and S(O)₂NR^(e)R^(e),wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-14 memberedheteroaryl, C₃₋₁₄ cycloalkyl, 4-14 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-14 membered heterocycloalkyl)-C₁₋₄alkyl- of R^(d) are each optionally substituted with 1, 2, or 3independently selected R^(f) substituents; each R^(e) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(e) are eachoptionally substituted with 1, 2 or 3 independently selected R^(f)substituents; each R^(b) substituent is independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NOH)R^(c), C(═NOH)NR^(c), C(═NCN)NR^(c)R^(c),NR^(c)C(═NCN)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c), —P(O)R^(c)R^(c), —P(O)(OR^(c))(OR^(c)), —B(OH)₂, —B(OR^(c))₂and S(O)₂NR^(c)R^(c); wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(b) are each further optionally substituted with 1, 2 or 3independently selected R^(d) substituents; each R^(c) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) are each optionallysubstituted with 1, 2, 3, 4, or 5 independently selected R^(f)substituents; each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,halo, CN, NHOR^(g), OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g),C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g),NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g),C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g),S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g),—P(O)R^(g)R^(g), —P(O)(OR^(g))(OR^(g)), —B(OH)₂, —B(OR^(g))₂ andS(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are eachoptionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(n) substituents; each R^(n) is substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(o), OR^(o), SR^(o),C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o),NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o),NR^(o)C(O)OR^(o), C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o),S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o),NR^(o)S(O)₂NR^(o)R^(o), —P(O)R^(o)R^(o), —P(O)(OR^(o))(OR^(o)), —B(OH)₂,—B(OR^(o))₂ and S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- of R^(n) are each optionally substituted with 1, 2 or 3independently selected R^(q) substituents; each R^(g) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) are each optionallysubstituted with 1, 2, or 3 independently selected R^(p) substituents;each R^(p) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(r),OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r),OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r), —P(O)R^(r)R^(r),—P(O)(OR^(r))(OR^(r)), —B(OH)₂, —B(OR^(r))₂ and S(O)₂NR^(r)R^(r),wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(p) is optionally substituted with 1,2 or 3 independently selected R^(q) substituents; or any two R^(a)substituents together with the boron, phosphorus or nitrogen atom towhich they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3independently selected R^(h) substituents; each R^(h) is independentlyselected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i),NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i),OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), —P(O)R^(i)R^(i),—P(O)(OR^(i))(OR^(i)), —B(OH)₂, —B(OR^(i))₂ and S(O)₂NR^(i)R^(i),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- ofR^(h) are each further optionally substituted by 1, 2, or 3independently selected R^(j) substituents; each R^(j) is independentlyselected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl,4-7 membered heterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, CN, NHOR^(k), OR^(k), SR^(k),C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k), OC(O)NR^(k)R^(k),NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k), NR^(k)C(O)NR^(k)R^(k),NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k), NR^(k)C(═NR^(k))NR^(k)R^(k),S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k), NR^(k)S(O)₂R^(k),NR^(k)S(O)₂NR^(k)R^(k), —P(O)R^(k)R^(k), —P(O)(OR^(k))(OR^(k)), —B(OH)₂,—B(OR^(k))₂ and S(O)₂NR^(k)R^(k), wherein the C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, 4-7 memberedheterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄haloalkoxy of R^(j) are each optionally substituted with 1, 2 or 3independently selected R^(q) substituents; or two R^(h) groups attachedto the same carbon atom of the 4- to 10-membered heterocycloalkyl takentogether with the carbon atom to which they are attached form a C₃₋₆cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatomsas ring members selected from O, N or S; or any two R^(c) substituentstogether with the boron, phosphorus or nitrogen atom to which they areattached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents; or any two R^(e) substituents together with theboron, phosphorus or nitrogen atom to which they are attached form a 4-,5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 independently selected R^(h) substituents;or any two R^(g) substituents together with the boron, phosphorus ornitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(h) substituents; or any two R^(i)substituents together with the boron, phosphorus or nitrogen atom towhich they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents, or 1, 2, or 3 independentlyselected R^(q) substituents; or any two R^(k) substituents together withthe boron, phosphorus or nitrogen atom to which they are attached form a4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 independently selected R^(h) substituents,or 1, 2, or 3 independently selected R^(q) substituents; or any twoR^(o) substituents together with the boron, phosphorus or nitrogen atomto which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; or any two R^(r) substituentstogether with the boron, phosphorus or nitrogen atom to which they areattached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents; each R^(i), R^(k), R^(o) or R^(r) is independentlyselected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl,C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7 memberedheterocycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl of R^(i), R^(k), R^(o)or R^(r) are each optionally substituted with 1, 2 or 3 independentlyselected R^(q) substituents; each R^(q) is independently selected fromhalo, OH, CN, —COOH, NH₂, —NH—C₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, phenyl,5-6 membered heteroaryl, 4-6 membered heterocycloalkyl and C₃₋₆cycloalkyl, wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6membered heterocycloalkyl, and 5-6 membered heteroaryl of R^(q) are eachoptionally substituted with 1, 2 or 3 substituents independentlyselected from halo, OH, CN, —COOH, NH₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀ cycloalkyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl; the subscript m is aninteger of 0, 1, 2 or 3; the subscript n is an integer of 0, 1, 2 or 3;each subscript q is independently an integer of 1, 2, 3 or 4; and thesubscript s is an integer of 1, 2, 3 or
 4. 3. The compound of claim 1,having Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein: ring A is 5- to 14-membered heteroaryl, 4- to 14-memberedheterocycloalkyl, C₆₋₁₀ aryl or C₃₋₁₄ cycloalkyl, wherein the 5- to14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each has1-4 heteroatoms as ring members selected from N, O and S, wherein the Nor S atom as ring members is optionally oxidized and one or more carbonatoms as ring members are each optionally replaced by a carbonyl group;and wherein ring A is optionally substituted with 1, 2, 3, 4 or 5 R⁶substituents; L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, O, —(CR¹⁴R¹⁵)_(q)—,—(CR¹⁴R¹⁵)_(q)—O—, —O(CR¹⁴R¹⁵)_(q)—, —NR¹³—, —(CR¹⁴R¹⁵)_(q)—NR¹³—,—NR¹³—(CR¹⁴R¹⁵)_(q)—, —CH═CH—, —C≡C—, —SO₂NR¹³—, —NR¹³SO₂—,—NR¹³SO₂NR¹³—, —NR¹³C(O)O—, —OC(O)NR¹³— or —NR¹³C(O)NR¹³—; R³ is methyl,halo, CN or C₁₋₄ haloalkyl; R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or—N(C₁₋₄ alkyl)₂; R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;R⁶ and R¹⁷ are each independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NOH)R^(a), C(═NOH)NR^(a),C(═NCN)NR^(a)R^(a), NR^(a)C(═NCN)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁶ and R¹⁷ are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents; or two R⁶ substituents attached to the same ring carbonatom taken together with the ring carbon atom to which they are attachedform spiro C₃₋₆ cycloalkyl or spiro 4- to 7-membered heterocycloalkyl,each of which is optionally substituted with 1, 2, or 3 independentlyselected R^(f) substituents; each R¹³ is independently H, C₁₋₆ haloalkylor C₁₋₆ alkyl optionally substituted with a substituent selected fromC₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH,—COOH, NH₂, —NHC₁₋₄ alkyl and —N(C₁₋₄ alkyl)₂; R¹⁴ and R¹⁵ are eachindependently selected from H, halo, CN, OH, —COOH, C₁₋₄ alkyl, C₁₋₄alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and4-6 membered heterocycloalkyl of R¹⁴ or R¹⁵ are each optionallysubstituted with 1, 2, or 3 independently selected R^(q) substituents;or R¹⁴ and R¹⁵ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5-, 6- or7-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 independently selected R^(q) substituents; each R^(a) isindependently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14 memberedheteroaryl, 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-,and (4-14 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14membered heteroaryl, 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl- and (4-14 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(a) areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(d) substituents; each R^(d) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₄cycloalkyl, 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-,(4-14 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e),SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e),OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NOH)NR^(e)R^(e),NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e),NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-14 membered heteroaryl,C₃₋₁₄ cycloalkyl, 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and (4-14 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(d) areeach optionally substituted with 1, 2, or 3 independently selected R^(f)substituents; each R^(e) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(e) are each optionally substitutedwith 1, 2 or 3 independently selected R^(f) substituents; each R^(b)substituent is independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NOH)R^(c), C(═NOH)NR^(c), C(═NCN)NR^(c)R^(c),NR^(c)C(═NCN)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c); wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(b) are each further optionally substituted with 1, 2 or 3independently selected R^(d) substituents; each R^(c) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) are each optionallysubstituted with 1, 2, 3, 4, or 5 independently selected R^(f)substituents; each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,halo, CN, NHOR^(g), OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g),C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g),NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g),C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g),S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g),and S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are eachoptionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(n) substituents; each R^(n) is substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(o), OR^(o), SR^(o),C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o),NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o),NR^(o)C(O)OR^(o), C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o),S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o),NR^(o)S(O)₂NR^(o)R^(o), and S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- of R^(n) are each optionally substituted with 1, 2 or 3independently selected R^(q) substituents; each R^(g) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) are each optionallysubstituted with 1, 2, or 3 independently selected R^(p) substituents;each R^(p) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(r),OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r),OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) and S(O)₂NR^(r)R^(r), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(p) is optionally substituted with 1,2 or 3 independently selected R^(q) substituents; or any two R^(a)substituents together with the nitrogen atom to which they are attachedform a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl groupoptionally substituted with 1, 2 or 3 independently selected R^(h)substituents; each R^(h) is independently selected from C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i), NHOR^(i), C(O)R^(i),C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i),NR^(i)R^(i), NR^(i)C(O)R^(i), NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i),C(═NR^(i))NR^(i)R^(i), NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i),S(O)NR^(i)R^(i), S(O)₂R^(i), NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i),and S(O)₂NR^(i)R^(i), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(h) are each further optionallysubstituted by 1, 2, or 3 independently selected R^(j) substituents;each R^(j) is independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,NHOR^(k), OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k),OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR)NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k), whereinthe C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-memberedheteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy of R^(j) are each optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents; ortwo R^(h) groups attached to the same carbon atom of the 4- to10-membered heterocycloalkyl taken together with the carbon atom towhich they are attached form a C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S; or any two R^(c) substituents together with the nitrogen atom towhich they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; or any two R^(e) substituentstogether with the nitrogen atom to which they are attached form a 4-,5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 independently selected R^(h) substituents;or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; or any two R^(i) substituentstogether with the nitrogen atom to which they are attached form a 4-,5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 independently selected R^(h) substituents;or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; or any two R^(o) substituentstogether with the nitrogen atom to which they are attached form a 4-,5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 independently selected R^(h) substituents;or any two R^(r) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; each R^(i), R^(k), R^(o) orR^(r) is independently selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, whereinthe C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl,4-7 membered heterocycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl of R^(i),R^(k), R^(o) or R^(r) are each optionally substituted with 1, 2 or 3independently selected R^(q) substituents; each R^(q) is independentlyselected from halo, OH, CN, —COOH, NH₂, —NH—C₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl and C₃₋₆ cycloalkyl, wherein the C₁₋₆ alkyl, phenyl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl of R^(q) are each optionally substituted with 1, 2 or 3substituents independently selected from halo, OH, CN, —COOH, NH₂, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl;the subscript m is an integer of 0, 1, 2 or 3; the subscript n is aninteger of 0, 1, 2 or 3; each subscript q is independently an integer of1, 2, 3 or 4; and the subscript s is an integer of 1, 2, 3 or
 4. 4. Thecompound of claim 1, having Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein: ring A is 5- to 14-membered heteroaryl, 4- to 14-memberedheterocycloalkyl, C₆₋₁₀ aryl or C₃₋₁₄ cycloalkyl, wherein the 5- to14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each has1-4 heteroatoms as ring members selected from N, O and S, wherein the Nor S atom as ring members is optionally oxidized and one or more carbonatoms as ring members are each optionally replaced by a carbonyl group;and wherein ring A is optionally substituted with 1, 2, 3, 4 or 5independently selected R⁶ substituents; L is a bond, —C(O)NR¹³—,—NR¹³C(O)—, O, —(CR¹⁴R¹⁵)_(q)—, —(CR¹⁴R¹⁵)_(q)—O—, —O(CR¹⁴R¹⁵)_(q)—,—NR¹³—, —(CR¹⁴R¹⁵)_(q)—NR¹³—, —NR¹³—(CR¹⁴R¹⁵)_(q)—, —CH═CH—, —C≡C—,—SO₂NR¹³—, —NR¹³SO₂—, —NR¹³SO₂NR¹³—, —NR¹³C(O)O—, —OC(O)NR¹³— or—NR¹³C(O)NR¹³—; R³ is methyl, halo, CN or C₁₋₄ haloalkyl; R⁴ is C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH,—COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂; R⁵ is C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂,—NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂; R⁶ and R¹⁷ are each independentlyselected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14 memberedheteroaryl, 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-,(4-14 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a),NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a),OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a),NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NOH)R^(a),C(═NOH)NR^(a), C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a),C(═NCN)NR^(a)R^(a), NR^(a)C(═NCN)NR^(a)R^(a), NR^(a)S(O)R^(a),NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a),S(O)₂R^(a), and S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl,4-14 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14membered heterocycloalkyl)-C₁₋₄ alkyl- of R⁶ and R¹⁷ are each optionallysubstituted with 1, 2, 3, 4 or 5 independently selected R^(b)substituents; each R¹³ is independently H, C₁₋₆ haloalkyl or C₁₋₆ alkyloptionally substituted with a substituent selected from C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂,—NHC₁₋₄ alkyl and —N(C₁₋₄ alkyl)₂; R¹⁴ and R¹⁵ are each independentlyselected from H, halo, CN, OH, —COOH, C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and4-6 membered heterocycloalkyl of R¹⁴ or R¹⁵ are each optionallysubstituted with 1, 2, or 3 independently selected R^(q) substituents;or R¹⁴ and R¹⁵ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5-, 6- or7-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 R^(q) substituents; each R^(a) is independently selectedfrom H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl,4-14 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionallysubstituted with 1, 2, 3, 4, or 5 independently selected R^(d)substituents; each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₄ cycloalkyl,4-14 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e),SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e),OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NOH)NR^(e)R^(e),NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e),NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-14 membered heteroaryl,C₃₋₁₄ cycloalkyl, 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and (4-14 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(d) areeach optionally substituted with 1, 2, or 3 independently selected R^(q)substituents; each R^(e) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(e) are each optionally substitutedwith 1, 2 or 3 independently selected R^(q) substituents; each R^(b)substituent is independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NOH)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), C(═NCN)NR^(c)R^(c),NR^(c)C(═NCN)NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c); wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(b) are each further optionally substituted with 1, 2 or 3independently selected R^(d) substituents; each R^(c) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) are each optionallysubstituted with 1, 2, 3, 4, or 5 independently selected R^(d)substituents; or any two R^(a) substituents together with the nitrogenatom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3independently selected R^(h) substituents; or any two R^(c) substituentstogether with the nitrogen atom to which they are attached form a 4-,5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 independently selected R^(h) substituents;or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; each R^(h) is independentlyselected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i),NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i),OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- ofR^(h) are each further optionally substituted by 1, 2, or 3independently selected R^(j) substituents; each R^(j) is independentlyselected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl,4-7 membered heterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, NHOR^(k), OR^(k), SR^(k),C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k), OC(O)NR^(k)R^(k),NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k), NR^(k)C(O)NR^(k)R^(k),NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k), NR^(k)C(═NR)NR^(k)R^(k),S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k), NR^(k)S(O)₂R^(k),NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k), wherein the C₁₋₄ alkyl,C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, 4-7 memberedheterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄haloalkoxy of R^(j) are each optionally substituted with 1, 2 or 3independently selected R^(q) substituents; each of R^(i) and R^(k) isindependently selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl,5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, wherein theC₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7membered heterocycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl of R^(i) orR^(k) are each optionally substituted with 1, 2 or 3 independentlyselected R^(q) substituents; each R^(q) is independently selected fromhalo, OH, CN, —COOH, NH₂, —NH—C₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, phenyl,5-6 membered heteroaryl, 4-6 membered heterocycloalkyl and C₃₋₆cycloalkyl, wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6membered heterocycloalkyl, and 5-6 membered heteroaryl of R^(q) are eachoptionally substituted with 1, 2 or 3 substituents selected from halo,OH, CN, —COOH, NH₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, phenyl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6membered heterocycloalkyl; the subscript m is an integer of 0, 1, 2 or3; the subscript n is an integer of 0, 1, 2 or 3; each subscript q isindependently an integer of 1, 2, 3 or 4; and the subscript s is aninteger of 1, 2, 3 or
 4. 5. The compound of claim 1, having Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein: ring A is 5- to 10-membered heteroaryl, 4- to 11-memberedheterocycloalkyl, C₆₋₁₀ aryl or C₃₋₁₀ cycloalkyl, wherein the 5- to10-membered heteroaryl and 4- to 11-membered heterocycloalkyl each has1-4 heteroatoms as ring members selected from N, O and S, wherein the Nor S atom as ring members is optionally oxidized and one or more carbonatoms as ring members are each optionally replaced by a carbonyl group;and wherein ring A is optionally substituted with 1, 2, 3, 4 or 5 R⁶substituents; L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, O, —(CR¹⁴R¹⁵)_(q)—,—(CR¹⁴R¹⁵)_(q)—O—, —O(CR¹⁴R¹⁵)_(q)—, —NR¹³—, —(CR¹⁴R¹⁵)_(q)—NR¹³—,—NR¹³—(CR¹⁴R¹⁵)_(q)—, —CH═CH—, —C≡C—, —SO₂NR¹³—, —NR¹³SO₂—, —NR¹³C(O)O—or —NR¹³C(O)NR¹³—; R³ is methyl, halo, CN or C₁₋₄ haloalkyl; R⁴ is C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH,—COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂; R⁵ is C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂,—NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂; R⁶ and R¹⁷ are each independentlyselected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a),NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a),OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a),NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a),C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a),NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a),S(O)₂R^(a), and S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R⁶ and R¹⁷ are each optionallysubstituted with 1, 2, 3, 4 or 5 R^(b) substituents; or two R⁶substituents attached to the same ring carbon atom taken together withthe ring carbon atom to which they are attached form spiro C₃₋₆cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each of which isoptionally substituted with 1, 2, or 3 independently selected R^(f)substituents; each R¹³ is independently H, C₁₋₆ haloalkyl or C₁₋₆ alkyloptionally substituted with a substituent selected from C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂,—NHC₁₋₄ alkyl and —N(C₁₋₄ alkyl)₂; R¹⁴ and R¹⁵ are each independentlyselected from H, halo, CN, OH, —COOH, C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and4-6 membered heterocycloalkyl of R¹⁴ or R¹⁵ are each optionallysubstituted with 1, 2, or 3 independently selected R^(q) substituents;or R¹⁴ and R¹⁵ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5- or6-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 R^(q) substituents; each R^(a) is independently selectedfrom H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionallysubstituted with 1, 2, 3, 4, or 5 R^(d) substituents; each R^(d) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),and S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are each optionally substitutedwith 1, 2, or 3 independently selected R^(f) substituents; each R^(e) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(e) are each optionally substituted with 1, 2 or 3 independentlyselected R^(f) substituents; each R^(b) substituent is independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂,NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c); wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(b) are each further optionally substituted with 1, 2 or 3independently selected R^(d) substituents; each R^(c) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) are each optionallysubstituted with 1, 2, 3, 4, or 5 R^(f) substituents; each R^(f) isindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g), OR^(g),SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(n) substituents; each R^(n) is substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(o), OR^(o),SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o),OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR^(o))NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), and S(O)₂NR^(o)R^(o), whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(n) are each optionally substitutedwith 1, 2 or 3 independently selected R^(q) substituents; each R^(g) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) are eachoptionally substituted with 1, 2, or 3 R^(p) substituents; each R^(p) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(r), OR^(r),SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r),OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) and S(O)₂NR^(r)R^(r), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(p) is optionally substituted with 1,2 or 3 R^(q) substituents; or any two R^(a) substituents together withthe nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-,9- or 10-membered heterocycloalkyl group optionally substituted with 1,2 or 3 R^(h) substituents; each R^(h) is independently selected fromC₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl,5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i), NHOR^(i), C(O)R^(i),C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i),NR^(i)R^(i), NR^(i)C(O)R^(i), NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i),C(═NR^(i))NR^(i)R^(i), NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i),S(O)NR^(i)R^(i), S(O)₂R^(i), NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i),and S(O)₂NR^(i)R^(i), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl,5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(h) are each further optionallysubstituted by 1, 2, or 3 R^(j) substituents; each R^(j) isindependently selected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-memberedheteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, NHOR^(k), OR^(k), SR^(k),C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k), OC(O)NR^(k)R^(k),NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k), NR^(k)C(O)NR^(k)R^(k),NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k), NR^(k)C(═NR)NR^(k)R^(k),S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k), NR^(k)S(O)₂R^(k),NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k), wherein the C₁₋₄ alkyl,C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, 4-6 memberedheterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄haloalkoxy of R^(j) are each optionally substituted with 1, 2 or 3independently selected R^(q) substituents; or two R^(h) groups attachedto the same carbon atom of the 4- to 10-membered heterocycloalkyl takentogether with the carbon atom to which they are attached form a C₃₋₆cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatomsas ring members selected from O, N or S; or any two R^(c) substituentstogether with the nitrogen atom to which they are attached form a 4-,5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with1, 2, or 3 independently selected R^(h) substituents; or any two R^(e)substituents together with the nitrogen atom to which they are attachedform a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 independently selected R^(h) substituents;or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents; or any two R^(i) substituents together with thenitrogen atom to which they are attached form a 4-, 5-, 6-, or7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; or any two R^(k) substituentstogether with the nitrogen atom to which they are attached form a 4-,5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with1, 2, or 3 independently selected R^(h) substituents; or any two R^(o)substituents together with the nitrogen atom to which they are attachedform a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 independently selected R^(h) substituents;or any two R^(r) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents; each R^(i), R^(k), R^(o) or R^(r) is independentlyselected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl,C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7 memberedheterocycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl of R^(i), R^(k), R^(o)or R^(r) are each optionally substituted with 1, 2 or 3 R^(q)substituents; each R^(q) is independently selected from halo, OH, CN,—COOH, NH₂, —NH—C₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ alkylthio, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, phenyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl and C₃₋₆ cycloalkyl, whereinthe C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl,and 5-6 membered heteroaryl of R^(q) are each optionally substitutedwith 1, 2 or 3 substituents selected from halo, OH, CN, —COOH, NH₂, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl;the subscript m is an integer of 0, 1, 2 or 3; the subscript n is aninteger of 0, 1, 2 or 3; each subscript q is independently an integer of1, 2, 3 or 4; and the subscript s is an integer of 1, 2, 3 or
 4. 6. Thecompound of claim 1, or a pharmaceutically acceptable salt or astereoisomer thereof, wherein: any two R^(i) substituents together withthe nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-,9- or 10-membered heterocycloalkyl group optionally substituted with 1,2, or 3 independently selected R^(q) substituents; or any two R^(k)substituents together with the nitrogen atom to which they are attachedform a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 independently selected R^(q)substituents.
 7. The compound of any of claim 1, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein (1) when L is—C(O)NH—, ring A is not4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl; (2) when L is a bond,ring A is not [1,2,4]triazolo[1,5-a]pyridin-2-yl; (3) when L is —NH—,ring A is not 1,7-naphthyridin-8-yl or pyrido[3,2-d]pyrimidin-4-yl; or(4) when L is —C(O)NH—, ring A is not 2-pyridyl.
 8. The compound ofclaim 1, having Formula (Ia):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein: one of R¹ and R² is —(CR⁸R⁹)_(p)—NR¹⁰R¹¹ and the other is H,C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH,—COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂, wherein the C₁₋₄ alkyl andC₁₋₄ alkoxy of R¹ or R² is optionally substituted with 1 or 2substituents independently selected from C₁₋₄ alkoxy, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, —C(O)NH₂, NH₂, —NHC₁₋₄ alkyl and—N(C₁₋₄ alkyl)₂; R⁷ is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂,wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy are each optionally substitutedwith 1 or 2 substituents independently selected from CN, halo or—C(O)NH₂; R⁸ and R⁹ are each independently selected from H, halo, CN,OH, —COOH, C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl, wherein the C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl,5-6 membered heteroaryl and 4-6 membered heterocycloalkyl of R⁸ or R⁹are each optionally substituted with 1, 2 or 3 independently selectedR^(q) substituents; or R⁸ and R⁹ taken together with the carbon atom towhich they are attached form 3-, 4-, 5- or 6-membered cycloalkyl or 4-,5-, 6- or 7-membered heterocycloalkyl, each of which is optionallysubstituted with 1 or 2 R^(q) substituents; or R⁸ and R¹⁰ taken togetherwith the atoms to which they are attached form 4-, 5-, 6- or 7-memberedheterocycloalkyl, having zero to one additional heteroatoms as ringmembers selected from O, N or S, wherein the 4-, 5-, 6- or 7-memberedheterocycloalkyl formed by R⁸ and R¹⁰ are each optionally substitutedwith 1 or 2 R^(q) substituents; R¹⁰ and R¹¹ are each independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₆ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,—C(O)R^(g), —C(O)OR^(g), —C(O)NR^(g)R^(g), —SO₂R^(g) and—SO₂NR^(g)R^(g), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₆ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R¹⁰ or R¹¹ are each optionallysubstituted with 1, 2, or 3 independently selected R^(d) substituents;or R¹⁰ and R¹¹ taken together with the nitrogen atom to which they areattached form 4-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-memberedheterocycloalkyl, wherein the 4-11 membered heterocycloalkyl is eachoptionally substituted with 1, 2 or 3 R^(f) substituents; R¹² is H, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH,—COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂; and the subscript p is aninteger of 1, 2, 3 or
 4. 9. The compound of claim 8, having Formula(II):

or a pharmaceutically acceptable salt or a stereoisomer thereof.
 10. Thecompound of claim 8, having Formula (IIa):

or a pharmaceutically acceptable salt or a stereoisomer thereof.
 11. Thecompound of claim 8, having Formula (IIb):

or a pharmaceutically acceptable salt or a stereoisomer thereof.
 12. Thecompound of claim 8, having Formula (IIb-1):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein: ring A is 5- to 10-membered heteroaryl, 4- to 11-memberedheterocycloalkyl or C₆₋₁₀ aryl, wherein the 5- to 10-membered heteroaryland 4- to 11-membered heterocycloalkyl each has 1-4 heteroatoms as ringmembers selected from N, O and S, wherein the N or S atom as ringmembers is optionally oxidized and one or more carbon atoms as ringmembers are each optionally replaced by a carbonyl group; and whereinring A is optionally substituted with 1, 2 or 3 R⁶ substituents; and Lis a bond, —C(O)NH—, —NH— or —OCH₂—, wherein the carbonyl group in the—C(O)NH— linkage or the oxygen atom in the —OCH₂— linkage is attached toring A.
 13. The compound of claim 8, having Formula (III):

or a pharmaceutically acceptable salt or a stereoisomer thereof.
 14. Thecompound of claim 8, having Formula (IIIa):

or a pharmaceutically acceptable salt or a stereoisomer thereof.
 15. Thecompound of claim 8, having Formula (IIIb):

or a pharmaceutically acceptable salt or a stereoisomer thereof.
 16. Thecompound of claim 8, having Formula (IIc):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein: X¹, X², X³, X⁴, X⁵ and X⁶ are each independently N or CH, withthe proviso that X¹, X⁵ and X⁶ are not simultaneously N; R¹³ is H orC₁₋₄ alkyl; and the subscript r is an integer of 1, 2 or
 3. 17. Thecompound of claim 8, having Formula (IIc-1):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or
 3. 18. The compound of claim 8,having Formula (IIc-2):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or
 3. 19. The compound of claim 8,having Formula (IIc-3):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinR¹³ is H or C₁₋₄ alkyl; and the subscript r is an integer of 1, 2 or 3.20. The compound of claim 8, having Formula (IIc-4):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or
 3. 21. The compound of claim 8,having Formula (IId):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein: R¹³ is H or C₁₋₄ alkyl; R¹⁸ is H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R¹⁸ are each optionallysubstituted with 1, 2, or 3 R^(b) substituents; and the subscript t isan integer of 0, 1 or
 2. 22. The compound of claim 16, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein R¹³is H.
 23. The compound of claim 8, having Formula (IIe):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or
 3. 24. The compound of claim 8,having Formula (IIf):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or
 3. 25. The compound of claim 8,having Formula (IIf-1):

or a pharmaceutically acceptable salt or a stereoisomer thereof.
 26. Thecompound of claim 8, having Formula (IIg):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript t is an integer of 0, 1 or
 2. 27. The compound of claim 8,having Formula (IIh):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or
 3. 28. The compound of claim 8,having Formula (IIj):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or
 3. 29. The compound of claim 8,having Formula (IIk):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or
 3. 30. The compound of claim 8,having Formula (IIm):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or
 3. 31. The compound of claim 8,having Formula (IIn):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or
 3. 32. The compound of claim 8,having Formula (IIo):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or
 3. 33. The compound of claim 8,having Formula (IIp):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is an integer of 1, 2 or
 3. 34. The compound of claim 8,or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinL is —C(O)NH—.
 35. The compound of claim 1, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein L is —NH—.
 36. Thecompound of claim 1, or a pharmaceutically acceptable salt or astereoisomer thereof, wherein ring A is selected from:

wherein each subscript r is an integer of 1, 2, 3, 4 or 5; R¹⁶ is C₁₋₆alkyl; and the wavy line indicates the point of attachment to L.
 37. Thecompound of claim 1, or a pharmaceutically acceptable salt or astereoisomer thereof, wherein ring A is selected from:

wherein the subscript r is an integer of 1, 2, 3, 4 or
 5. 38. Thecompound of claim 1, or a pharmaceutically acceptable salt or astereoisomer thereof, wherein ring A is selected from:

wherein the subscript r is an integer of 1, 2 or
 3. 39. The compound ofclaim 1, or a pharmaceutically acceptable salt or a stereoisomerthereof, wherein ring A is selected from:

wherein the subscript r is an integer of 1, 2 or
 3. 40. The compound ofclaim 1, or a pharmaceutically acceptable salt or a stereoisomerthereof, wherein R⁶ is H, C₁₋₆ alkyl, 2-hydroxyethyl,1-(2-hydroxyethyl)azetidin-3-yl, pyrrolidin-2-yl,3-(dimethylamino)propanoyl, 1-methylpyrrolidine-2-carbonyl,2-(4-methylpiperazin-1-yl)acetyl, 2-(isopropylamino)acetyl,2-((R)-3-hydroxypyrrolidin-1-yl)acetyl,2-((S)-3-hydroxypyrrolidin-1-yl)acetyl,2-(3-hydroxypyrrolidin-1-yl)acetyl, 2-(azetidin-1-yl)acetyl,2-(ethyl(methyl)amino)acetyl,2-((S)-3-hydroxy-3-methylpyrrolidin-1-yl)acetyl,2-((R)-3-hydroxy-3-methylpyrrolidin-1-yl)acetyl,(S)-(1-methylpyrrolidin-2-yl)methanoyl,2-(3-hydroxyazetidin-1-yl)acetyl, 2-((R)-3-hydroxyazetidin-1-yl)acetyl,2-((S)-3-hydroxyazetidin-1-yl)acetyl,2-(3-hydroxy-3-methylazetidin-1-yl)acetyl,2-((R)-3-hydroxy-3-methylazetidin-1-yl)acetyl,2-((S)-3-hydroxy-3-methylazetidin-1-yl)acetyl, 2-(azetidin-1-yl)acetyl,pyrrolidin-1-ylmethyl, azetidin-1-ylmethyl,3-hydroxyazetidin-1-yl)methyl, (R)-3-hydroxyazetidin-1-yl)methyl,(S)-3-hydroxyazetidin-1-yl)methyl,2-(3-hydroxy-3-methylpyrrolidin-1-yl)methyl,2-((S)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl,2-((R)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl,1-((R)-3-hydroxypyrrolidin-1-yl)ethyl,(((S)-2-hydroxypropyl)amino)methyl, (((R)-2-hydroxypropyl)amino)methyl,((-2-hydroxypropyl)amino)methyl, (2-hydroxyethyl)amino)methyl,(3-carboxypyrrolidin-1-yl)methyl, (R)-(3-carboxypyrrolidin-1-yl)methyl,(S)-(3-carboxypyrrolidin-1-yl)methyl, (3-hydroxypyrrolidin-1-yl)methyl,(R)-(3-hydroxypyrrolidin-1-yl)methyl,(S)-(3-hydroxypyrrolidin-1-yl)methyl, (2-hydroxyethylamino)methyl,(2-hydroxy-2-methylpropylamino)methyl, 2-(dimethylamino)ethanoyl,2-(3-carboxyazetidin-1-yl)ethanoyl,(R)-2-(3-carboxyazetidin-1-yl)ethanoyl,(S)-2-(3-carboxyazetidin-1-yl)ethanoyl,2-(2-carboxypiperidin-1-yl)ethanoyl,(R)-2-(2-carboxypiperidin-1-yl)ethanoyl,(S)-2-(2-carboxypiperidin-1-yl)ethanoyl,2-(3-carboxypyrrolidin-1-yl)ethanoyl,(S)-2-(3-carboxypyrrolidin-1-yl)ethanoyl,(R)-2-(3-carboxypyrrolidin-1-yl)ethanoyl, (5-cyanopyridin-3-yl)methoxy,halo or CN.
 41. The compound of claim 1, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein R⁶ is2-(3-hydroxypyrrolidin-1-yl)ethyl,(R)-2-(3-hydroxypyrrolidin-1-yl)ethyl,(S)-2-(3-hydroxypyrrolidin-1-yl)ethyl, 4,5-dihydro-1H-imidazol-2-yl,(S)-(1-hydroxybutan-2-ylamino)methyl,(S)-(1-hydroxybutan-2-ylamino)methyl, (1-hydroxybutan-2-ylamino)methyl,(S)-(1-hydroxypropan-2-ylamino)methyl,(R)-(1-hydroxypropan-2-ylamino)methyl,(1-hydroxypropan-2-ylamino)methyl, (methylamino)methyl,(1-hydroxy-2-methylpropan-2-ylamino)methyl,(1-hydroxycyclopropyl)methylamino)methyl,(4-carboxypiperidin-1-yl)methyl,(R)-(3-carboxy-3-methylpyrrolidin-1-yl)methyl,(S)-(3-carboxy-3-methylpyrrolidin-1-yl)methyl,(3-carboxy-3-methylpyrrolidin-1-yl)methyl,2-(isopropyl(methyl)amino)acetyl, 2-(ethyl(methyl)amino)acetyl,2-((cyclopropylmethyl)(methyl)amino)acetyl,2-(4-ethylpiperazin-1-yl)acetyl, 2-(4-methylpiperazin-1-yl)acetyl,2-((2-hydroxyethyl)(methyl)amino)acetyl,2-(((R)-1-hydroxypropan-2-yl)(methyl)amino)acetyl,2-(((S)-1-hydroxypropan-2-yl)(methyl)amino)acetyl,2-((-1-hydroxypropan-2-yl)(methyl)amino)acetyl, (4-boronophenyl)methyl,2-(methyl(methyl)amino)acetyl, 2-(4-hydroxypiperidin-1-yl)acetyl,2-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)acetyl,(4-carboxycyclohexyl)methyl, trans-(4-carboxycyclohexyl)methyl,cis-(4-carboxycyclohexyl)methyl,(3-carboxybicyclo[1.1.1]pentan-1-yl)methyl,3-carboxy-3-methylcyclobutyl, 4-carboxycycloheptanyl,2-(4-carboxycyclohexan-1-yl)ethyl, (4-carboxycyclohexan-1-yl)methyl,(4-carboxybicyclo[2.2.1]heptan-1-yl)methyl or(4-carboxy-4-methylcyclohexyl)methyl.
 42. The compound of claim 1, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein L isa bond, —CH₂—, —NH—, —CH═CH— or —C(O)NH—, wherein the carbonyl group inthe —C(O)NH— linkage is attached to ring A.
 43. The compound of claim 1,or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript m is
 0. 44. The compound of claim 1, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein the subscript n is 1and R⁵ is halo or C₁₋₄ alkyl.
 45. The compound of claim 1, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein R³and R⁵ are each independently halo, methyl or CN.
 46. The compound ofclaim 1, or a pharmaceutically acceptable salt or a stereoisomerthereof, wherein R³ is methyl, CN or Cl.
 47. The compound of claim 8, ora pharmaceutically acceptable salt or a stereoisomer thereof, whereinR¹² is H, halo, CN, C₁₋₄ alkyl or C₁₋₄ alkoxy.
 48. The compound of claim8, or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein R⁷ is H, halo, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy or C₁₋₄ haloalkoxy,wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy of R⁷ are each optionallysubstituted with CN.
 49. The compound of claim 8, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein R⁷ is CN or halo. 50.The compound of claim 8, or a pharmaceutically acceptable salt or astereoisomer thereof, wherein R² is cyanomethoxy.
 51. The compound ofclaim 8, or a pharmaceutically acceptable salt or a stereoisomerthereof, wherein R¹ is cyanomethoxy.
 52. The compound of claim 8, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein thesubscript p is
 1. 53. The compound of claim 8, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein R⁸ and R⁹ are each H.54. The compound of claim 8, or a pharmaceutically acceptable salt or astereoisomer thereof, wherein R¹⁰ is H or CH₃.
 55. The compound of claim8, or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein R¹¹ is 2-hydroxyethyl, 2-carboxyethyl,[1-(hydroxymethyl)cyclopropyl]methyl,[1-(hydroxymethyl)cyclobutyl]methyl or 2-(dimethylamino)-2-oxo-ethyl.56. The compound of claim 8, or a pharmaceutically acceptable salt or astereoisomer thereof, wherein R¹¹ is 3-carboxycyclopentyl,(R)-3-carboxycyclopentyl, (S)-3-carboxycyclopentyl,2-carboxycyclopentyl, (R)-2-carboxycyclopentyl,(S)-2-carboxycyclopentyl, 3-carboxycyclobutyl,4-(carboxymethyl)cyclohexyl, 4-carboxybicyclo[2.2.1]heptan-1-yl,2-hydroxypropyl or 1-hydroxy-2-propyl.
 57. The compound of claim 8, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein—NR¹⁰R¹¹ is (2-hydroxyethyl)amino, (2-carboxyethyl)amino,2-carboxy-1-piperidinyl, 2-oxooxazolidin-3-yl,[1-(hydroxymethyl)cyclopropyl]methylamino,[1-(hydroxymethyl)cyclobutyl]methylamino, 3-carboxypyrrolidin-1-yl,(R)-3-carboxypyrrolidin-1-yl, (S)-3-carboxypyrrolidin-1-yl,(S)-2-carboxypyrrolidin-1-yl, (R)-2-carboxypyrrolidin-1-yl,2-carboxypyrrolidin-1-yl, (1-carboxyethyl)amino,(R)-(1-carboxyethyl)amino, (S)-(1-carboxyethyl)amino,3-methyl-3-carboxypyrrolidin-1-yl, 4-carboxypiperidin-1-yl,3-carboxy-azetidin-1-yl, (R)-3-carboxy-azetidin-1-yl,(S)-3-carboxy-azetidin-1-yl, (2-hydroxyethyl)(methyl)amino,[2-(dimethylamino)-2-oxo-ethyl]amino,(R)-3-methyl-3-carboxypyrrolidin-1-yl,(S)-3-methyl-3-carboxypyrrolidin-1-yl, (1-carboxyethyl)amino,(4-carboxycyclohexyl)amino, 3-(methylaminocarbonyl)pyrrolidin-1-yl,(R)-3-(methylaminocarbonyl)pyrrolidin-1-yl,(S)-3-(methylaminocarbonyl)pyrrolidin-1-yl,3-(2-hydroxyethylaminocarbonyl)pyrrolidin-1-yl,(R)-3-(2-hydroxyethylaminocarbonyl)pyrrolidin-1-yl,(S)-3-(2-hydroxyethylaminocarbonyl)pyrrolidin-1-yl,2-(methylcarbonylamino)ethylamino,3-(2-hydroxyethylcarbonylamino)pyrrolidin-1-yl,(R)-3-(2-hydroxyethylcarbonylamino)pyrrolidin-1-yl,(S)-3-(2-hydroxyethylcarbonylamino)pyrrolidin-1-yl,(R)-3-hydroxypyrrolidin-1-yl, (S)-3-hydroxypyrrolidin-1-yl, or3-hydroxypyrrolidin-1-yl.
 58. The compound of claim 8, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein—NR¹⁰R¹¹ is (2-hydroxyethyl)amino, (2-carboxyethyl)amino,2-carboxy-1-piperidinyl, 2-oxooxazolidin-3-yl,[1-(hydroxymethyl)cyclopropyl]methylamino,[1-(hydroxymethyl)cyclobutyl]methylamino, 3-carboxypyrrolidin-1-yl,(S)-2-carboxypyrrolidin-1-yl, (S)-3-methyl-3-carboxypyrrolidin-1-yl,4-carboxypiperidin-1-yl, 3-carboxy-azetidin-1-yl,(2-hydroxyethyl)(methyl)amino or [2-(dimethylamino)-2-oxo-ethyl]amino.59. The compound of claim 8, or a pharmaceutically acceptable salt or astereoisomer thereof, wherein —NR¹⁰R¹¹ is5-carboxy-2-azabicyclo[2.2.1]heptan-2-yl,4-carboxy-2-azabicyclo[2.1.1]hexan-2-yl,6-carboxy-2-azaspiro[3.3]heptan-2-yl,3-carboxy-3-methoxymethylpyrrolidin-1-yl,(R)-3-carboxy-3-methoxymethylpyrrolidin-1-yl,(S)-3-carboxy-3-methoxymethylpyrrolidin-1-yl,4-carboxy-2-azabicyclo[2.1.1]hexan-2-yl,3-methanesulfamoylpyrrolidin-1-yl,5-carboxy-2-azabicyclo[2.2.1]heptan-2-yl,5-hydroxy-2-azabicyclo[2.2.1]heptan-2-yl, pyrrolidin-1-yl, (1R,3S)-3-carboxycyclopentan-1-ylamino, (1R,3R)-3-carboxycyclopentan-1-ylamino, (1S,3S)-3-carboxycyclopentan-1-ylamino, (1S,3R)-3-carboxycyclopentan-1-ylamino, (1R,2R)-2-carboxycyclopentan-1-ylamino, (1S,2S)-2-carboxycyclopentan-1-ylamino, (1R,2S)-2-carboxycyclopentan-1-ylamino, (1S,2R)-2-carboxycyclopentan-1-ylamino, trans-3-carboxycyclobutan-1-ylamino,cis-3-carboxycyclobutan-1-ylamino,trans-4-(carboxymethyl)cyclohexan-1-ylamino,cis-4-(carboxymethyl)cyclohexan-1-ylamino,4-carboxybicyclo[2.2.1]heptan-1-ylamino, (R)-2-hydroxypropylamino,(S)-2-hydroxypropylamino, (R)-3-hydroxy-propan-2-ylamino or(S)-3-hydroxy-propan-2-ylamino.
 60. The compound of claim 1, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein ringA is 2-pyridyl, optionally substituted with 1, 2, 3, or 4 independentlyselected R⁶ substituents.
 61. The compound of claim 1 selected from:(S)-1-((7-chloro-2-(2′-chloro-3′-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2-methyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicacid;(S)-1-((7-chloro-2-(2′-chloro-3′-(5-(((S)-3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-2-methyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicacid;(S)-1-((7-chloro-2-(3′-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicacid;(S)-1-((7-chloro-2-(3′-((3-(((2-hydroxy-2-methylpropyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicacid;(S)-1-((7-chloro-2-(3′-((3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicacid;3-(((7-chloro-2-(3′-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)amino)propanoicacid;(2S,2′S)-1,1′-(((2,2′-dimethyl-[1,1′-biphenyl]-3,3′-diyl)bis(6-(cyanomethoxy)benzo[d]oxazole-2,5-diyl))bis(methylene))bis(piperidine-2-carboxylic acid);(S)-1-((7-chloro-2-(2′-chloro-2-methyl-3′-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicacid; andN-(2-chloro-3′-(7-chloro-5-(((2-hydroxyethyl)amino)methyl)benzo[d]oxazol-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide;or a pharmaceutically acceptable salt or a stereoisomer thereof.
 62. Thecompound of claim 1 selected from:(S)-1-((7-chloro-2-(3′-(7-chloro-5-(((S)-3-hydroxypyrrolidin-1-yl)methyl)benzol[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-chloro-2-(2,2′-dimethyl-3′-(pyrido[4,3-b]pyrazin-5-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(pyrido[4,3-b]pyrazin-5-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(pyrido[3,2-d]pyrimidin-4-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(2′-chloro-2-methyl-3′-(pyrido[4,3-b]pyrazin-5-ylamino)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(2′-chloro-2-methyl-3′-(pyrido[3,4-b]pyrazin-8-ylamino)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-chloro-2-(3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((7-chloro-2-(3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-chloro-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((7-chloro-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-3-((7-chloro-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methylamino)propanoicacid;(S)-3-(((7-chloro-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)(methyl)amino)propanoicacid;(S)-1-((7-chloro-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylicacid;(S)-1-((7-chloro-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((7-cyano-2-(3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((7-cyano-2-(3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicacid;(S)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-chloro-2-(2′-chloro-3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(2′-chloro-3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(2′-chloro-2-methyl-3′-(3-((2-oxooxazolidin-3-yl)methyl)-1,7-naphthyridin-8-ylamino)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((7-chloro-2-(2′-chloro-3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((2-(2′-chloro-3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(2′-chloro-3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(S)-1-((7-cyano-2-(3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-2-carboxylicacid;(S)-1-((7-cyano-2-(3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((7-cyano-2-(3′-(5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((7-cyano-2-(3′-(5-isopropyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((7-cyano-2-(3′-(5-cyclopropyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((7-cyano-2-(3′-(5-(3,3-difluorocyclobutyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((7-cyano-2-(3′-(5-((S)-2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;3-(((7-chloro-2-(3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)(methyl)amino)propanoic acid;(R)-1-((7-chloro-2-(2′-chloro-2-methyl-3′-(4-(methylamino)piperidin-1-yl)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-chloro-2-(2′-chloro-3′-(4-(cyclopropylamino)piperidin-1-yl)-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-chloro-2-(2′-chloro-3′-(4-((1s,3s)-3-hydroxycyclobutylamino)piperidin-1-yl)-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-chloro-2-(2′-chloro-3′-(4-((1-(hydroxymethyl)cyclobutyl)methylamino)piperidin-1-yl)-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(2′-chloro-3′-(4-((1s,3s)-3-hydroxycyclobutylamino)piperidin-1-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(2′-chloro-3′-(4-(ethyl(2-hydroxyethyl)amino)piperidin-1-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(2′-chloro-3′-(4-(ethyl((1s,3s)-3-hydroxycyclobutyl)amino)piperidin-1-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((2-(2′-chloro-3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((7-cyano-2-(3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2′-fluoro-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((2-(2′-chloro-3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylicacid;(R)-1-((2-(2′-chloro-3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((2-(2′-chloro-2-methyl-3′-(5-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(2′-chloro-2-methyl-3′-(5-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(2′-chloro-3′-(5-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(2′-chloro-2-methyl-3′-(6-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(2′-chloro-3′-(6-ethyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-chloro-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-chloro-2-(3′-(5-ethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-chloro-2-(3′-(5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(3R)-1-((7-chloro-2-(3′-(5-(1-hydroxypropan-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(cyclopropylmethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(3R)-1-((7-cyano-2-(3′-(5-(1-hydroxypropan-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((7-cyano-2-(3′-(5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;1-((7-cyano-2-(3′-(5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicacid;(R)-1-((2-(2-chloro-2′-methyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-chloro-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-chloro-2-(2,2′-dimethyl-3′-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-chloro-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((7-chloro-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;1-((7-chloro-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicacid;(R)-1-((7-chloro-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(4,4,5-trimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((7-chloro-2-(2′-chloro-3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-chloro-2-(2′-chloro-3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((2-(2′-chloro-3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(2′-chloro-3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicacid;(R)-3-((7-cyano-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methylamino)-2,2-dimethylpropanoicacid; and(R)-1-((2-(2′-chloro-3′-(6-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid; or a pharmaceutically acceptable salt or a stereoisomer thereof.63. The compound of claim 1 selected from:(R)-1-((2-(2′-chloro-3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;1-((2-(2′-chloro-3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylicacid;(S)-2-((2-(2′-chloro-3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methylamino)propanoicacid;(1R,4R)-4-((2-(2′-chloro-3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methylamino)cyclohexanecarboxylicacid;(S)-1-((2-(2′-chloro-2-methyl-3′-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((2-(2′-chloro-3′-(5-(2-hydroxyethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((2-(2′-chloro-3′-(1,5-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(2′-chloro-3′-(5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(3-(1-(2-hydroxyethyl)azetidin-3-yl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(3R)-1-((2-(2′-chloro-2-methyl-3′-(3-(pyrrolidin-2-yl)-1,7-naphthyridin-8-ylamino)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(3R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(3-(pyrrolidin-2-yl)-1,7-naphthyridin-8-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(3R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(3-(pyrrolidin-2-yl)-1,7-naphthyridin-8-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-3-((7-cyano-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methylamino)propanoicacid;(R)-1-((7-cyano-2-(3′-(3-fluoro-4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(2′-chloro-3′-(6-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-N-methylpyrrolidine-3-carboxamide;(R)-1-((2-(2′-chloro-3′-(6-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-N-(2-hydroxyethyl)pyrrolidine-3-carboxamide;(R)-1-((7-cyano-2-(3′-(5-(2-(dimethylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(3-(dimethylamino)propanoyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(5-((S)-1-methylpyrrolidine-2-carbonyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(5-(2-(4-methylpiperazin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-(dimethylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-(isopropylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-((R)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-((S)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(3′-(5-(2-(azetidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-(ethyl(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-((S)-3-hydroxy-3-methylpyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-((R)-3-hydroxy-3-methylpyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-N-methylpyrrolidine-3-carboxamide;N-(2-(((7-cyano-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)amino)ethyl)acetamide;(R)-1-((7-cyano-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-N-(2-hydroxyethyl)pyrrolidine-3-carboxamide;5-(((2-hydroxyethyl)amino)methyl)-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile;(R)-5-((3-hydroxypyrrolidin-1-yl)methyl)-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile;(R)-1-((7-cyano-2-(3′-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;1-((7-cyano-2-(3′-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicacid;(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(5-(methyl-L-prolyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(3-(dimethylamino)propanoyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-((R)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-(3-hydroxyazetidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-((S)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-(3-hydroxy-3-methylazetidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(3′-(5-(2-(azetidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-(2-(2-(3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)pyrrolidine-3-carboxylicacid;(R)-1-(2-(2-(3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)pyrrolidine-3-carboxylicacid;(S)-1-(2-(2-(3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)piperidine-2-carboxylicacid;(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(3-(pyrrolidin-1-ylmethyl)-1,7-naphthyridin-8-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(3′-(3-(azetidin-1-ylmethyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(3-((3-hydroxyazetidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(3-(((S)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(3R)-1-((7-cyano-2-(3′-(3-(1-((R)-3-hydroxypyrrolidin-1-yl)ethyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((8-(3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((2-(2′-chloro-3′-(5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(2′-chloro-3′-(5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((7-cyano-2-(3′-((4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-((4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-((3-((((S)-2-hydroxypropyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-((3-((((R)-2-hydroxypropyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-chloro-2-(3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)phenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-(4-((3′-(5-(((R)-3-carboxypyrrolidin-1-yl)methyl)-7-chlorobenzo[d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylicacid;(R)-1-((7-chloro-2-(3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(((2-hydroxyethyl)amino)methyl)phenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((5-(2-chloro-3′-(7-chloro-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl)pyrrolidine-3-carboxylicacid;(S)-1-((7-cyano-2-(3′-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)imidazo[1,2-a]pyrazin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid; and1-((7-chloro-2-(2′-chloro-3′-((5-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-3-methylpyrazin-2-yloxy)methyl)-2-methylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid; or a pharmaceutically acceptable salt or a stereoisomer thereof.64. The compound of claim 1, selected from:1-((2-(2′-chloro-2-methyl-3′-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylicacid;(R)-1-((2-(2′-chloro-3′-(5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylicacid;1-((2-(2′-chloro-3′-(5-(2-hydroxyethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid;(R)-1-((2-(2′-chloro-3′-(5-((R)-2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((2-(2′-chloro-3′-(1,5-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid;(3R)-1-((2-(2′-chloro-3′-(1,6-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(3R)-1-((2-(2′-chloro-2-methyl-3′-(1,5,6-trimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(3R)-1-((2-(2′-chloro-2-methyl-3′-(1,5,6-trimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;1-((2-(2′-chloro-2-methyl-3′-(1,5,6-trimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid;(3R)-1-((2-(2′-chloro-3′-(1,6-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;1-((2-(2′-chloro-3′-(1,6-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid;2-(2-chloro-3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1,5,6-trimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylicacid;(R)-1-((7-cyano-2-(3′-(3-(4,5-dihydro-1H-imidazol-2-yl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(2-chloro-3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2′-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(1R,3S)-3-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl) methylamino)cyclopentanecarboxylicacid;(1S,3R)-3-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl) methylamino)cyclopentanecarboxylicacid; (R)-4-(2-((7-cyano-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methylamino)ethyl)benzoic acid; cis-4-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methylamino)cyclohexanecarboxylicacid;2-((R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidin-3-yl)aceticacid;2-((S)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidin-3-yl)aceticacid;(1R,2S)-2-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl) methylamino) cyclopentanecarboxylicacid; 2-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-2-azabicyclo[2.2.1]heptane-5-carboxylic acid;2-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-2-azaspiro[3.3]heptane-6-carboxylicacid; (R)-2-((7-cyano-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid;(1S,2S)-2-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl) methylamino)cyclopentanecarboxylicacid; cis-3-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methylamino)cyclobutane carboxylic acid;trans-3-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methylamino)cyclobutane carboxylic acid;(1S,3S)-3-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methylamino)cyclopentane carboxylic acid;(R)-4-((7-cyano-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methylamino)bicyclo[2.2.1] heptane-1-carboxylic acid;2-(trans-4-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methylamino)cyclohexyl)aceticacid; 1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-(methoxy methyl)pyrrolidine-3-carboxylicacid; (R)-1-((7-cyano-2-(3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid;(R)-1-((2-(2′-chloro-3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid; (R)-1-((2-(2′-chloro-3′-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid;(R)-1-((7-cyano-2-(3′-(3-((2-hydroxyethylamino)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(3-(((2-hydroxyethyl)(methyl)amino)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(3-(((S)-2-hydroxypropylamino)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(3-(((R)-2-hydroxypropylamino)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(3-(pyrrolidin-1-ylmethyl)-1,7-naphthyridin-8-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(3-(((S)-1-hydroxybutan-2-ylamino)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(3-(((S)-1-hydroxypropan-2-ylamino)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid; (R)-1-((7-cyano-2-(3′-(3-(((R)-1-hydroxypropan-2-ylamino)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid;(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(3-((methylamino)methyl)-1,7-naphthyridin-8-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(3-((1-hydroxy-2-methylpropan-2-ylamino)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid;(R)-1-((7-cyano-2-(3′-(3-(((1-hydroxycyclopropyl)methylamino)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(3-(((S)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(S)-1-((7-cyano-2-(3′-(3-((1-hydroxypropan-2-ylamino)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylicacid;(R)-1-((7-cyano-2-(3′-(3-((1-hydroxypropan-2-ylamino)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl) benzo[d]oxazol-5-yl)methyl) piperidine-4-carboxylic acid;(R)-1-((7-cyano-2-(3′-(3-((2-hydroxypropylamino)methyl)-1,7-naphthyridin-8-yl amino)-2,2′-dimethylbiphenyl-3-yl)benzo [d]oxazol-5-yl)methyl) piperidine-4-carboxylic acid;(S)-1-((7-cyano-2-(3′-(3-((2-hydroxypropylamino)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylicacid;(R)-1-((7-cyano-2-(3′-(7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(S)-1-((7-cyano-2-(3′-(7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-3-carboxylicacid; (R)-1-((7-cyano-2-(3′-(7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylicacid;(R)-1-((7-cyano-2-(3′-(7-(((S)-2-hydroxypropylamino)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(7-(pyrrolidin-1-ylmethyl)pyrido[3,2-d]pyrimidin-4-ylamino)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((8-(3′-(7-cyano-5-(((S)-2-hydroxypropylamino)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylicacid; (R)-1-((8-(3′-(7-cyano-5-(((S)-1-hydroxypropan-2-ylamino)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylicacid; (S)-1-((8-(3′-(7-cyano-5-((2-hydroxypropylamino)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)piperidine-4-carboxylicacid; (S)-1-((8-(3′-(7-cyano-5-((1-hydroxypropan-2-ylamino)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)piperidine-4-carboxylicacid; (R)-1-((8-(3′-(7-cyano-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)piperidine-4-carboxylicacid; (R)-1-((8-(3′-(7-cyano-5-(((S)-1-hydroxypropan-2-ylamino)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((8-(3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2′-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-(isopropyl(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-(ethyl(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-((cyclopropylmethyl)(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;2-((7-cyano-2-(3′-(5-(2-(ethyl(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-2-azabicyclo[2.1.1]hexane-4-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-((S)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-((R)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-(4-ethylpiperazin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-((2-hydroxyethyl)(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-(((R)-1-hydroxypropan-2-yl)(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-(((S)-1-hydroxypropan-2-yl)(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-(3-hydroxyazetidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-(cis-3-hydroxycyclobutylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-(trans-3-hydroxycyclobutylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;2-((7-cyano-2-(3′-(5-(2-((2-hydroxyethyl)(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-2-azaspiro[3.3]heptane-6-carboxylicacid;2-((7-cyano-2-(3′-(5-(2-(((R)-1-hydroxypropan-2-yl)(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-2-azaspiro[3.3]heptane-6-carboxylicacid;2-((7-cyano-2-(3′-(5-(2-(((S)-1-hydroxypropan-2-yl)(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-2-azaspiro[3.3]heptane-6-carboxylicacid;2-((7-cyano-2-(3′-(5-(2-((S)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-2-azaspiro[3.3]heptane-6-carboxylicacid;2-((7-cyano-2-(3′-(5-(2-((R)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-2-azaspiro[3.3]heptane-6-carboxylicacid;2-((7-cyano-2-(3′-(5-(2-(dimethylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-2-azabicyclo[2.1.1]hexane-4-carboxylicacid;1-((7-cyano-2-(3′-(5-(2-(dimethylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylicacid;2-((7-cyano-2-(3′-(5-(2-(dimethylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-2-azabicyclo[2.2.1]heptane-5-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-N-(methylsulfonyl)pyrrolidine-3-carboxamide;1-((2-(2′-chloro-3′-(6-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)azetidine-3-carboxylicacid;(R)-4-((2-(2-chloro-3′-(7-cyano-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)phenylboronicacid;(R)-1-((7-cyano-2-(3′-(5-(N-ethyl-N-methylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;2-((7-cyano-2-(3′-(5-(N-ethyl-N-methylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-2-azabicyclo[2.1.1]hexane-4-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(N-ethyl-N-methylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;1-((7-cyano-2-(3′-(5-(N-ethyl-N-methylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;1-((7-cyano-2-(3′-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-((R)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(N-isopropyl-N-methylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-(4-hydroxypiperidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(2-(4-hydroxypiperidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;2-((7-cyano-2-(3′-(5-(2-(4-hydroxypiperidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-2-azabicyclo[2.2.1]heptane-5-carboxylicacid;(R)-1-((7-cyano-2-(3′-(5-(N-(2-hydroxyethyl)-N-methylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;2-((7-cyano-2-(2,2′-dimethyl-3′-(5-(2-(4-methylpiperazin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-2-azabicyclo[2.2.1]heptane-5-carboxylicacid;(R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(5-(2-(4-methylpiperazin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;(3R)-1-((7-cyano-2-(2,2′-dimethyl-3′-(5-(2-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((2-(2′-chloro-3′-(5-(2-((R)-3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(3-(((S)-1-hydroxypropan-2-ylamino)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;(R)-1-((7-cyano-2-(3′-(3-(((R)-1-hydroxypropan-2-ylamino)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylicacid;1-((7-cyano-2-(3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylicacid;(R)-1-((7-cyano-2-(3′-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid;trans-4-((2-(2-chloro-3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylicacid;(R)-3-((2-(2-chloro-3′-(7-cyano-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylicacid;(R)-3-(2-(2-chloro-3′-(7-cyano-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)-1-methylcyclobutanecarboxylicacid;4-(2-(2-chloro-3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)cycloheptanecarboxylicacid;(R)-4-(2-(2-(2-chloro-3′-(7-cyano-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexanecarboxylicacid;cis-4-((2-(2-chloro-3′-(7-cyano-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylicacid;(R)-4-((2-(2-chloro-3′-(7-cyano-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)bicyclo[2.2.1]heptane-1-carboxylicacid;(R)-4-((2-(2-chloro-3′-(7-cyano-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)-1-methylcyclohexanecarboxylicacid;trans-4-((2-(2-chloro-3′-(7-cyano-5-((5-hydroxy-2-azabicyclo[2.2.1]heptan-2-yl)methyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylicacid; andtrans-4-((2-(2-chloro-3′-(7-cyano-5-(pyrrolidin-1-ylmethyl)benzo[d]oxazol-2-yl)-2′-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexanecarboxylicacid, or a pharmaceutically acceptable salt or a stereoisomer thereof.65. The compound of claim 8, or a pharmaceutically acceptable salt or astereoisomer thereof, wherein: ring A is 5- to 10-membered heteroaryl or4- to 11-membered heterocycloalkyl, wherein the 5- to 10-memberedheteroaryl and 4- to 11-membered heterocycloalkyl each has 1-4heteroatoms as ring members selected from N, O and S, wherein the N or Satom as ring members is optionally oxidized and one or more carbon atomsas ring members are each optionally replaced by a carbonyl group; andwherein ring A is optionally substituted with 1, 2, or 3 R⁶substituents; L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, O, or —NR¹³—; one ofR¹ and R² is —(CR⁸R⁹)_(p)—NR¹⁰R¹¹ and the other is H, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, or OH, wherein theC₁₋₄ alkyl and C₁₋₄ alkoxy of R¹ or R² is optionally substituted with 1or 2 substituents independently selected from C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, NH₂, —NHC₁₋₄ alkyl and —N(C₁₋₄alkyl)₂; R³ is methyl or halo; R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, CN, halo, or OH; R⁵ is C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, or OH; each R⁶ isindependently selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, CN, OR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), NHR^(a), NR^(a)R^(a), andNR^(a)C(O)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₃₋₁₀ cycloalkyl of R⁶ are each optionally substituted with 1 or 2 R^(b)substituents; R⁷ is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, CN, halo, or OH; R⁸ and R⁹ are each independently selectedfrom H, halo, CN, OH, —COOH, C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl,—N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy; R¹⁰ and R¹¹ areeach independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,—C(O)R^(g), —C(O)OR^(g), and —C(O)NR^(g)R^(g), wherein the C₁₋₆ alkyland C₁₋₆ haloalkyl of R¹⁰ or R¹¹ are each optionally substituted with 1,2 or 3 independently selected R^(f) substituents; or R¹⁰ and R¹¹ takentogether with the nitrogen atom to which they are attached form 4-, 5-,6- or 7-membered heterocycloalkyl, wherein the 4-, 5-, 6- or 7-memberedheterocycloalkyl is optionally substituted with 1 or 2 R^(h)substituents; R¹² is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, CN, halo, or OH; each R¹³ is independently H, C₁₋₆ haloalkylor C₁₋₆ alkyl optionally substituted with a substituent selected fromC₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, orOH; each R^(a) is independently selected from H, CN, C₁₋₆ alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₁₀ cycloalkyl, whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₁₀ cycloalkyl ofR^(a) are each optionally substituted with 1 or 2 R^(d) substituents;each R^(d) is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,C₁₋₆ haloalkyl, halo, CN, NH₂, OR^(e), C(O)R^(e), C(O)NR^(e)R^(e),C(O)OR^(e), NHR^(e), NR^(e)R^(e), and NR^(e)C(O)R^(e), wherein the C₁₋₆alkyl and C₃₋₁₀ cycloalkyl of R^(d) are each optionally substituted with1, 2, or 3 independently selected R^(f) substituents; each R^(e) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl; each R^(b) substituent is independently selected fromhalo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,CN, OH, NH₂, OR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), NHR^(c),NR^(c)R^(c), and NR^(c)C(O)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl-and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are eachfurther optionally substituted with 1 or 2 independently selected R^(d)substituents; each R^(c) is independently selected from H, C₁₋₆ alkyl,C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R^(c) are each optionally substitutedwith 1, 2, or 3 R^(f) substituents; each R^(f) is independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN,OR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), NHR^(g), NR^(g)R^(g),and NR^(g)C(O)R^(g); each R^(g) is independently selected from H, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; each R^(h) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(i), C(O)R^(i),C(O)NR^(i)R^(i), C(O)OR^(i), NHR^(i), NR^(i)R^(i), and NR^(i)C(O)R^(i);each R^(i) is independently selected from H, C₁₋₄ alkyl, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; the subscript m is aninteger of 0, 1 or 2; the subscript n is an integer of 0, 1, or 2; andthe subscript p is an integer of 1, 2, or
 3. 66. The compound claim 8,or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein: ring A is 5- to 10-membered heteroaryl, 4- to 11-memberedheterocycloalkyl, or C₆₋₁₀ aryl, wherein the 5- to 10-memberedheteroaryl and 4- to 11-membered heterocycloalkyl each has 1-4heteroatoms as ring members selected from N, O and S, wherein the N or Satom as ring members is optionally oxidized and one or more carbon atomsas ring members are each optionally replaced by a carbonyl group; andwherein ring A is optionally substituted with 1, 2, or 3 R⁶substituents; L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, —(CR¹⁴R¹⁵)_(q)—O—,—O(CR¹⁴R¹⁵)_(q)—, or —NR¹³—; one of R¹ and R² is —(CR⁸R⁹)_(p)—NR¹⁰R¹¹and the other is H, C₁₋₄ alkyl, or C₁₋₄ alkoxy, wherein the C₁₋₄ alkyland C₁₋₄ alkoxy of R¹ or R² is optionally substituted with 1 or 2substituents independently selected from C₁₋₄ alkoxy, CN, halo, OH, andNH₂; R³ is methyl or halo; R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, halo, orOH; R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, halo, or OH; each R⁶ isindependently selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, CN, OR^(a), NHR^(a), NR^(a)R^(a), C₃₋₁₀ cycloalkyl, 4-14membered heterocycloalkyl, (4-14 membered heterocycloalkyl)-C₁₋₄ alkyl-,CN, OR^(a), and C(O)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-14 membered heterocycloalkyl, and (4-14membered heterocycloalkyl)-C₁₋₄ alkyl- of R⁶ are each optionallysubstituted with 1 or 2 R^(b) substituents; each R¹³ is independently Hor C₁₋₆ alkyl; R¹⁴ and R¹⁵ are each independently selected from H andC₁₋₄ alkyl; R⁷ is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, halo, or OH; R⁸ and R⁹are each independently selected from H, halo, CN, OH, and C₁₋₄ alkyl;R¹⁰ and R¹¹ are each independently selected from H, C₁₋₆ alkyl, and C₁₋₆haloalkyl, wherein the C₁₋₆ alkyl and C₁₋₆ haloalkyl of R¹⁰ or R¹¹ areeach optionally substituted with 1, 2 or 3 independently selected R^(f)substituents; or R¹⁰ and R¹¹ taken together with the nitrogen atom towhich they are attached form 4-, 5-, 6- or 7-membered heterocycloalkyl,wherein the 4-, 5-, 6- or 7-membered heterocycloalkyl is optionallysubstituted with 1 or 2R^(h) substituents; R¹² is H or C₁₋₄ alkyl; eachR¹³ is independently H or C₁₋₆ alkyl; each R^(a) is independentlyselected from H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-14 memberedheterocycloalkyl, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-14membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, 4-14 membered heterocycloalkyl, (5-14 memberedheteroaryl)-C₁₋₄ alkyl- and (4-14 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(a) are each optionally substituted with 1 or 2 independentlyselected R^(d) substituents; each R^(d) is independently selected fromC₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-14 membered heterocycloalkyl, C₁₋₆haloalkyl, halo, CN, OR^(e), C(O)OR^(e), NHR^(e), and NR^(e)R^(e),wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, and 4-14 memberedheterocycloalkyl of R^(d) are each optionally substituted with 1, 2, or3 independently selected R^(f) substituents; each R^(e) is independentlyselected from H and C₁₋₆ alkyl; each R^(b) substituent is independentlyselected from halo, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, CN, OH, OR^(c),C(O)NR^(c)R^(c), C(O)OR^(c), NH₂, NHR^(c), NR^(c)R^(c), andNR^(c)C(O)R^(c); wherein the C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl of R^(b) are each furtheroptionally substituted with 1 or 2 independently selected R^(d)substituents; each R^(c) is independently selected from H, C₁₋₆ alkyl,and C₃₋₁₀ cycloalkyl, wherein C₁₋₆ alkyl and C₃₋₁₀ cycloalkyl are eachoptionally substituted with 1, 2, or 3 R^(f) substituents; each R^(f) isindependently selected from C₁₋₄ alkyl, halo, CN, OR^(g), C(O)R^(g),C(O)NR^(g)R^(g), C(O)OR^(g), and NR^(g)C(O)R^(g); each R^(g) isindependently selected from H and C₁₋₆ alkyl; each R^(h) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,halo, OR^(i), C(O)R^(i), C(O)NR^(i)R^(i), and C(O)OR^(i); each R^(i) isindependently selected from H and C₁₋₄ alkyl; the subscript m is aninteger of 0 or 1; the subscript n is an integer of 0 or 1; and thesubscript p is an integer of 1 or
 2. 67. The compound of claim 8, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein:ring A is 5- to 10-membered heteroaryl or 4- to 11-memberedheterocycloalkyl, wherein the 5- to 10-membered heteroaryl and 4- to11-membered heterocycloalkyl each has 1-4 heteroatoms as ring membersselected from N, O and S, wherein the N or S atom as ring members isoptionally oxidized and one or more carbon atoms as ring members areeach optionally replaced by a carbonyl group; and wherein ring A isoptionally substituted with 1 or 2 R⁶ substituents; L is a bond,—C(O)NR¹³—, —NR¹³C(O)—, or —NR¹³—; one of R¹ and R² is—(CR⁸R⁹)_(p)—NR¹⁰R¹¹ and the other is H, C₁₋₄ alkyl, or C₁₋₄ alkoxy,wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy of R¹ or R² is optionallysubstituted with 1 or 2 substituents independently selected from C₁₋₄alkoxy, CN, halo, OH, and NH₂; R³ is methyl or halo; R⁴ is C₁₋₄ alkyl,C₁₋₄ alkoxy, CN, halo, or OH; R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, halo,or OH; each R⁶ is independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, CN, OR^(a), NHR^(a), NR^(a)R^(a), and C₃₋₁₀cycloalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₃₋₁₀ cycloalkyl of R⁶ are each optionally substituted with 1 or 2 R^(b)substituents; R⁷ is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, halo, or OH; R⁸ andR⁹ are each independently selected from H, halo, CN, OH, and C₁₋₄ alkyl;R¹⁰ and R¹¹ are each independently selected from H, C₁₋₆ alkyl, and C₁₋₆haloalkyl, wherein the C₁₋₆ alkyl and C₁₋₆ haloalkyl of R¹⁰ or R¹¹ areeach optionally substituted with 1, 2 or 3 independently selected R^(f)substituents; or R¹⁰ and R¹¹ taken together with the nitrogen atom towhich they are attached form 4-, 5-, 6- or 7-membered heterocycloalkyl,wherein the 4-, 5-, 6- or 7-membered heterocycloalkyl is optionallysubstituted with 1 or 2 R^(h) substituents; R¹² is H or C₁₋₄ alkyl; eachR¹³ is independently H or C₁₋₆ alkyl; each R^(a) is independentlyselected from H, C₁₋₆ alkyl, and C₃₋₁₀ cycloalkyl optionally substitutedwith 1 or 2 R^(d) substituents; each R^(d) is independently selectedfrom C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₆ haloalkyl, halo, CN, OR andC(O)OR^(e), wherein the C₁₋₆ alkyl and C₃₋₁₀ cycloalkyl of R^(d) areeach optionally substituted with 1, 2, or 3 independently selected R^(f)substituents; each R^(e) is independently selected from H and C₁₋₆alkyl; each R^(b) substituent is independently selected from halo, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, CN, OH, NH₂, NHR^(c), NR^(c)R^(c), andNR^(c)C(O)R^(c); wherein the C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl of R^(b) are each furtheroptionally substituted with 1 or 2 independently selected R^(d)substituents; each R^(c) is independently selected from H and C₁₋₆ alkyloptionally substituted with 1, 2, or 3 R^(f) substituents; each R^(f) isindependently selected from C₁₋₄ alkyl, halo, CN, OR^(g), C(O)R^(g),C(O)NR^(g)R^(g), and C(O)OR^(g); each R^(g) is independently selectedfrom H and C₁₋₆ alkyl; each R^(h) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, OR^(i), C(O)R^(i),C(O)NR^(i)R^(i), and C(O)OR^(i); each R^(i) is independently selectedfrom H and C₁₋₄ alkyl; the subscript m is an integer of 0 or 1; thesubscript n is an integer of 0 or 1; and the subscript p is an integerof 1 or
 2. 68. A pharmaceutical composition comprising a compound ofclaim 1, or a pharmaceutically acceptable salt or a stereoisomerthereof, and one or more pharmaceutically acceptable excipient orcarrier.
 69. A method of inhibiting PD-1/PD-L1 interaction, said methodcomprising administering to a patient a compound of claim 1, or apharmaceutically acceptable salt or a stereoisomer thereof.
 70. A methodof treating a disease or disorder associated with inhibition ofPD-1/PD-L1 interaction, said method comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof claim 1, or a pharmaceutically acceptable salt or a stereoisomerthereof.
 71. A method of enhancing, stimulating and/or increasing theimmune response in a patient, said method comprising administering tothe patient in need thereof a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt or astereoisomer thereof.